Adrian0 G. Arguedas, MD Au&a A. Deveikis, MD Melvin I. Marks, MD Long
Beach
and Irvine,
California
Measles has become epidemic over most of the world, with an important increase in the number of cases and associated morbidity and mortality in the United States since 1986. The two major factors responsible for this rise in the number of cases are, first, the increase in unvaccinated preschool-age children and, second, vaccine nonresponders (approximately 5%). The highest attack rate occurred in teenagers (15 to 19 years old) and in nine states (82% of cases). This situation has prompted revised immunization recommendations for those counties reporting more than five cases of measles among preschool-age children during each of the previous 5 years. In these counties, a first dose with monovalent measles vaccine is recommended at 9 months of age, followed by a second dose with measles, mumps, and rubella vaccine at 15 months of age, and revaccination of all children at the time of school entry. Recent publications regarding the use of vitamin A and certain antiviral agents are encouraging and are discussed in the manuscript. All cases of measles should be reported and investigated promptly. A good outbreak-control program will depend on the rapid recognition of the disease, a team approach, and prompt vaccination or IgG administration to susceptible persons. (AM J INFECT CONTROL 1991:19:290-S)
Measles is an acute communicable disease characterized by fever, cough, coryza, conjunctivitis, an erythematous maculopapular rash, and a characteristic enanthem.‘, 2 Although clinical measles is epidemic over most of the world, its incidence was reduced in North America with the use of attenuated vaccines.3 However, an important increase in the number of cases and in associated morbidity and mortality has occurred in the United States since 1986.4-7 During the year 1989-90, 57 cases of complicated measles were admitted to Memorial Miller Children’s Hospital (0.5% of total admissions). This represented 236 in-hospital days and a total cost of $540,027. Among several factors implicated in this epidemic, the most important is that more than one third of American children are not fully immunized.4. 6*7
From the Department of Pediatrics, Division of Pediatric Infectious Diseases, Memorial Miller Children’s Hospital, Long Beach, and University of California, Irvine. Reprint requests: Adrian0 G. Arguedas, MD, Pediatric Infectious Diseases, Memorial Miller Children’s Hospital, 2801 Atlantic Ave., Long Beach, CA 90801-1428. 17/46/26263
290
ElWL@@Y
Measles virus is classified in the family of Pavarnyxoviridue, genus morbilliviruss It contains linear, negative-sense, single-stranded RNA, which codes for six virion structural proteins. The virus is very labile, inactivated by heat, ultraviolet light, lipid solvents such as ether and chloroform, and extreme degrees of acidity (pH lO). At room temperature there is a 60% loss in titers in 3 to 5 days.“, ’ Measles virus may be isolated in primary cultures of human embryonic or rhesus monkey kidney cultures. Cytopathic changes are usually visible in 5 to 10 days and consist of multinucleated giant cells with intranuclear inclusions.H CLIwloAL
AT
The clinical characteristics of the disease are different in patients with typical measles than in those with modified or atypical measles. Modified measles is defined as an infection that occurs in partially immune persons, whereas atypical measles is a clinical syndrome that occurs after exposure to natural measles in some subjects who were previously immunized with inactivated vaccine .‘, 3*’
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TYPICAL
Measles
1991
291
ILLNESS
The incubation period is approximately 10 to 15 days. The prodromal phase lasts between 1 and 3 days and is characterized by low-grade to moderate fever and respiratory symptoms that may cause the disease to be initially confused with a common cold. At this time the patient has a hacking cough, coryza, conjunctival inflammation, and photophobia. These almost always precede Koplik spots, the pathognomonic sign of measles, by 2 to 3 days. Koplik spots are grayish white dots, usually as small as grains of sand, with red areolae, that occur opposite the lower molars but may also be located irregularly over the rest of the buccal mucosa. They appear and disappear rapidly, usually within 12 to 18 hours. As they fade, there may remain red spotty discoloration of the mucosa. During the prodromal period, erythematous maculopapular lesions may be observed occasionally on the palate. At the end of the prodromal period, the posterior pharyngeal wall is usually erythematous and the patient may complain of sore throat.le3 The typical exanthem appears on about the fourteenth day after exposure, at about the peak of the respiratory symptoms and when the temperature is in the 39.5” C range. At this time the Koplik spots may have disappeared or may still be present, but these will disappear within the next 3 days. The measles exanthem first appears behind the ears and on the forehead (hairline). The spread of the rash is centrifugal from head to toe, being confluent in the face and discrete in the lower extremities (Fig. 1). Usually by the third day the rash has involved the face, neck, trunk, upper extremities, buttocks, and lower extremities. The rash is initially erythematous and maculopapular but progresses to confluence in the same manner as its spread. The exanthem begins to clear by the third to the fourth day, following the same centrifugal course of progression. As the rash fades, desquamation and a brownish discoloration occur and then disappear within 7 to 10 days.lT3 During the exanthem period, fever usually peaks by the second or third day of the rash and then falls over a Whour period. Fever that persists after the fourth day of the rash is suggestive of bacterial infection.3 Other general complaints, such as nasal discharge and conjunctivitis, also disappear by the time of defervescence. Cough usually loosens up with the appearance of the rash, but it is not uncommon for it to last 10 days or longer.‘* 3
Fig. 1. Typical measles. Note confluence per body.
of rash on up-
Pharyngitis and generalized lymphadenopathy, especially involving the cervical glands, are not uncommon findings and tend to resolve around the time the rash fades. Young children may occasionally have gastrointestinal complaints (diarrhea and vomiting), laryngitis, and croup.‘,4,5 MODIFIED
ILLNESS
Modified measles is characterized by a mild illness that usually follows the same sequence of events as typical measles. The mildness of this illness is usually due to the presence of specific measles antibodies in the affected child, either transplacentally acquired maternal antibodies in infants less than 9 months of age or antibodies produced by the administration of immune serum globulin to an exposed susceptible child. Less commonly, modified measles may be a manifestation of vaccine failure.3’ 9, lo Under these circumstances the prodromal period is shortened, with minimal cough, coryza, and low-grade fever. Koplik spots are usually ab-
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TaMe 1. Measles complications Early complications: Otitis media Laryngitis Laryngotracheitis Pneumonia Diarrhea Encephalitis Myocarditis Pericarditis Hemorrhagic measles Thrombocytopenic purpura Hepatitis Appendicitis Stevens-Johnson syndrome Late complications: Subacute sclerosing panencephalitis
sent; when they occur, they are few in number and transient. The exanthem follows the same distribution as in typical measles, but confluence is rare. Duration of illness is similar to that of the typical cases.‘, 3 ATYPICAL
IELWEEI
Atypical measles is a defined clinical entity that occurs in previously immunized persons. The majority of the reported cases are in persons who received the inactivated measles vaccine available in the United States from 1963 to 1967, but some cases also have been reported in children who received the live measles vaccine.‘, ‘l-l3 The incubation period is similar to that of typical cases (10 to 14 days), and the prodromal period is characterized by the sudden onset of high fever (40” C), headache, dry nonproductive cough, abdominal pain, and myalgia. Koplik spots are rare in atypical measles. The rash appears 2 to 3 days after the beginning of the prodromal period. Unlike typical measles, the rash first appears on the distal extremities and progresses in a cephalad direction.‘.” To date, measles virus has not been recovered from secretions of patients with atypical measles and, therefore, epidemiologic data suggest that patients with atypical measles are not contagious.3, 9 However, we believe that until further data are available, the same isolation procedures should be followed for these patients as for patients with typical measles. EPIDEYIOLOQY
Measles, a disease with worldwide distribution, is transmitted by direct contact with infec-
tious droplets or, less commonly, by airborne spread.‘, 3, 9 In the prevaccine era, measles was an epidemic disease with biennial cycles in LX-.ban areas, occurring mostly in preschooi aud young school-age children.” 3 The immunization program in the United States resulted initialiv in a 99% reduction in reported cases of measles. One third of the cases occurred in adolescents and young adults .9, I4 Since 1983, the number of measles cases reported to the Centers for Disease Control (CDC) increased annually until 1986, with a slight decrease in 1987 through 1989.” ’/ The highest attack rate (5.8 per 100,000) occurred in teenagers (15 to 19 years old) and in nine states that accounted for 82% of the total cases.” ” !I) Two major factors are responsible for this rise in the number of cases: (1) an increase in the number of unvaccinated preschool-age children, accounting for outbreaks in inner city areas, and (2) vaccine nonresponders (approximately s%f, accounting for outbreaks in highly immunized school-age populations.‘4, I7 These observations have prompted revised immunization r-ecommendations by the American Academy of Pediatrics and the CDC in an effort to raise ageappropriate immunity (see Prevention).“’ ” Epidemic measles is a winter and spring disease.3, 9 There is no gender difference, but some studies have suggested that boys are more prone to have complications, such as laryngitis, otitis media, pneumonia, and death.‘, IN,” Measles susceptibility does not vary by race, LILA, or blood type.*’ The disease is spread more commonly un-der crowded situations, as in day care centers, and morbidity and mortality are higher in immunocompromised hosts, in children under 2 years of age, and in malnourished children.3 “ ii COW’LICATIOBlS
Measles is an exanthema with high morbidity and mortality in malnourished and immunocompromised hosts. 1. 3 The chief complications of measles due to superinfection are otitis media and pneumonia (Table 1). Measles usually causes suppression of delayed hypersensitivity, leading to a transient reversal of previously positive skin testing for tuberculosis and histoplasmosis and sometimes to worsening or reactivation of mycobacterial infection.“” An exacerbation of fever (>38.5” C), change in blood count from leukopenia to leukocytosis, and development of malaise, pain, or prostration suggest a complicating bacterial infection.
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Measles 293
1991
Otitis media is the most common complication (5% to 10%) and is related to age (most common in children under 5 years).‘, 6. ’ The bacterial pathogens are similar to those seen in children without measles (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhaZis).3 Other upper respiratory tract infections, such as laryngitis, laryngotracheitis, or secondary bacterial infections of the cervical lymph nodes, are not uncommon and should be kept in mind.‘, 3 Pulmonary involvement in measles, caused by the measles virus itself, is very common.‘,3 In the majority of cases, when pneumonia is observed early in the course of the illness, measles is the cause; when this occurs farther into the disease (>3 to 4 days), secondary bacterial infection is usually implicated (Fig. 2). The roentgenographic appearance of measles viral pneumonitis is characterized by bilateral hyperinflation with diffuse infiltrates, more confluent in the hilum.‘s3 Although unilateral, segmental, and lobar pneumonias can be caused by measles virus, they are usually due to secondary bacterial pathogens,‘, 3, 2’ most commonly S. pneumoniae, H. influenzae, S. pyogenes, or Staphylococcus aureus.‘-3 Clinical manifestations of bacterial pneumonia appear late in the course of the disease and are characterized by high fever (>38.5” C), a productive cough, and progressive respiratory distress. Neurologic complications are more common in measles than in any of the other exanthems .3, 22,23 Encephalitis occurs about once in 600 to 1000 cases.3, 23 There is no correlation between the severity of measles and that of neurologic involvement or between the severity of the initial encephalitic process and the prognosis. Encephalitis usually occurs 2 days to 3 weeks after onset of the exanthem, beginning with high fever and convulsions and ending, in some cases, in coma.3, 22 It has been suggested that when encephalitis occurs early in the course of the disease, it is probably secondary to viral invasion of the central nervous system; when encephalitis occurs later, it is predominantly an immunologic phenomenon.3, 23 In most instances, examination of cerebrospinal fluid (CSF) will reveal a lymphocyte count of between 50 and 500/mm3 with an elevated protein concentration and a normal glucose CSF/serum ratio.‘,22 A normal CSF at the time of initial symptoms, however, does not rule out encephalitis and, if central nervous system
Fig. 2. Measles pneumonitis third day of infection.
in 7-month-old
infant on
(CNS) symptoms persist, should be repeated in 48 to 72 hours. The course of measles encephalitis may be brief, with recovery in about a week, or it may be prolonged and terminate in serious CNS impairment or death.3.22.23 No specific therapy is available at this time, and only supportive measures are recommended.‘, 3 Gastrointestinal complications are frequently seen in measles. In the United States from 1986 to 1989 about 4% to 17% of the patients with measles had diarrhea.4-7 In the majority of the cases this is self-limited and lasts between 5 and 7 days. Other than measles virus, no specific etiologic agent is implicated. Symptomatic therapy with close electrolyte and fluid monitoring is usually effective. In some instances, hospitalization is required because of poor fluid intake and secondary dehydration. If a bacterial pathogen is recovered (Shigella, Salmonella, or Campylobatter) from stools, specific antimicrobial therapy is recommended. Measles virus is also associated with subacute
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Table
2. Differential
diagnosis
Rubella Scarlet fever Drug rash Adenovirus infectlon Coxsackievirus infection Hemorrhagic varicella
of measles
Roseola infantum Epstein-Barr virus infectjon Kawasaki syndrome Echovirus infection Rickettsial Infection Meningococcal infection
sclerosing panencephalitis (SSPE), a progressing fatal neurologic condition seen mainly in late childhood.‘, 3, 24, 25 This complication occurs months to years after an attack of measles (1 per 100,000 infections) or, less commonly, after vaccination with live attenuated vaccine (1 per 1 ,OOO,OOOvaccinees) and causes intellectual deterioration, convulsive seizures, and motor abnormalities.3. ‘*, 24 Measles virus has been identified in brain tissue of these patients by electron microscopy, by demonstration of measles antigen through fluorescent antibody techniques, and by isolation of the agent in brain biopsy specimens. 3,23,26.*’ The mean incubation period from measles illness to onset of SSPE is 7 years, whereas for vaccinees in whom SSPE develops the mean incubation period is 3.3 years.3’ 24Boys are affected three times more commonly than girls, and in the United States SSPE is more prevalent in the southeastern part of the country and in children from farms.24 This suggests that some unknown extrinsic factors, unrelated to measles or to measles vaccine, may play an important role in the pathogenesis of this disease.3, 24 Measles has been associated with other, less common complications. Myocarditis and pericarditis occasionally occur, but clinical consequences are rare?’ Hemorrhagic measles, a severe, often fatal form of measles characterized by extensive bleeding from different organs, is rarely seen today, and little is known about its pathogenesis.3 Thrombocytopenic purpura is another bleeding disorder seen on occasion with measles, and its prognosis is usually good.3, *’ Less frequently, glomerulonephritis, StevensJohnson syndrome, hepatitis, appendicitis, ileocolitis, mesenteric lymphadenitis, and gangrene of the extremities are complications of measles .3”. 1,3 DlAt3WOSIS
The diagnosis of measles is usually made on clinical grounds and on the basis of exposure and immunization history. Laboratory confirmation
is rarely needed for typical cases but may be 01 value for the diagnosis of modified or atvpicai cases. During the prodromal stage, rnultinu. cleated giant cells can be seen in nasal mucos~~ smears and the white blood ceil count is lo\\ (2,000 to 4,000 cells/mm’) with a relative lymphocytosis (80% to 90%).‘, 3’ Measles infection can be specifically diagnosed bv virai iso lation in a tissue culture system (primary monkey kidney), by demonstration of measles antigen in exfoliated cells by the fluorescent antibody technique, by the demonstration ol hemagglutination-inhibiting test, complementfixation test, or neutralizing antibody titer increase in two sequential serum samples (3 weeks apart), or by a positive IgM measles-specific antibody during the acute phase or the first 2 weeks of the convalescent phase.‘, 1,9 For practical purposes, we recommend that in those cases in which the diagnosis cannot be made on clinical grounds serologic studies rather than viral cultures (low yield of positive results) should be pcrformed. Lumbar puncture in patients with measles encephalitis shows an increase in protein and a mild lymphocytosis with normal glucose.” In cases of subacute sclerosing panencephalitis (SSPE) the CSF will show a marked globulin elevation, predominantly IgG. In patients with SSPE, measles serum and CSF, HAI, and CF antibody titers are highly elevated (‘2 1 : 1 280).2”, ” Differential diagnosis of typical measles includes rubella, scarlet fever, drug rashes, roseola infantum, infectious mononucleosis, Kawasaki syndrome, and other viral infections (adenovirus, echovirus, and coxsackievirus infections) (Table 2).le3 Distinguishing features of rubella include its mild course, enlarged and usually tender postauricular and suboccipital nodes, normal blood count, and the usual absence of a prodromal period. Scarlet fever is usually ruled out by the presence of the Koplik spots and the typical rash seen in measles. Drug rashes may resemble the measles eruption, but a good history and the typical cephalocaudal progression of the measles rash will clarify the diagnosis. Roseola infantum is seldom seen in children over the age of 3, and it can usually be differentiated by its high initial temperature, the absence of Koplik spots, and the appearance of the rash simultaneously with defervescence. The differential diagnosis of atypical measles is similar to that of typical measles; however, the pleomorphism of the rash and the severity of
Volume 19 Number 6 December
Measles
1991
symptoms may suggest other entities, such as Rocky Mountain spotted fever, hemorrhagic varicella, drug allergy, secondary syphilis, typhus, or a meningococcal infection.‘! g A history of measles exposure and prior receipt of killed vaccine may suggest the diagnosis of atypical measles, but in the majority of cases serologic confirmation (serum HA1 + measles titers are very high) is necessary.
Table
3. Treatment
295
of measles
Symptomatic support Antimicrobials for secondary infection Consider vitamin A (Retinyl palmitate), 200,000 IU orally per day for 2 days, in malnourished children with severe measles Consider ribavirin (oral, nebulized, and/or intravenous) in patients with measles pneumonia, disseminated measles, or immunocompromised hosts (?)
TREATMENT
There is no specific treatment for uncomplicated measles (Table 3). Symptomatic support with antipyretics for high fever, bed rest, and adequate fluid intake are indicated. The patient should be protected from exposure to strong light when photophobic. Close observation for complications, such as secondary infections, is indicated. If otitis media or pneumonia develops, appropriate antimicrobial therapy should be started promptly. Such complications as encephalitis, giant cell pneumonia, and disseminated intravascular coagulation must be carefully assessed individually. Recently some studies have evaluated the value of vitamin A (400,000 IU of retinyl palmitate given orally) in children with severe measles.32-34This is based on the effect that vitamin A has on the maintenance of normal epithelial tissues and the fact that measles infects and damages the epithelium throughout the body, resulting in increased morbidity and mortality from respiratory and diarrhea1 causes. Although the idea seems very attractive, we believe that until this observation is confirmed, we could not recommend the routine use of vitamin A in wellnourished children. However, the benefits may outweigh the risks in a malnourished child with severe measles, and 200,000 IU of retinyl palmitate should be given orally for 2 days in an attempt to reduce morbidity and mortality. Although no specific antiviral therapy against measles is available, ribavirin (l-beta-Dribofuranosyl1,2,4 triazole-3-carboxamide) has shown in vitro and clinical activity against measles virus.35-36 Reports of patients with measles pneumonia, 37 disseminated measles,38 and SSPE3’ treated with ribavirin indicate that this drug may be considered in these situations, especially in immunocompromised hosts. More clinical trials are necessary before firm recommendations can be made. Immunoglobulin has no established benefit in the therapy of measles. A recent controlled clin-
Table
4. Prevention
of measles
Sltuatlon
Recommendation
Exposed susceptible person (~72 hr) Exposed susceptible person (>72 hr) or Contraindication for vaccine use *IgG dose for immunocompromised
Measles vaccine IgG 0.25 ml/kg IM*
host: 0.50 ml/kg IM.
ical trial in immunocompetent hosts failed to document any effect of the administration of intravenous immunoglobulin on the clinical course or the immune function recovery during the acute phase of the disease.40 In a single AIDS patient, however, the combined administration of intravenous IgG (400 mg/kg daily for 5 days) with ribavirin therapy was beneficial, and such treatment might be considered under these circumstances.38 At present there is no specific therapy for SSPE. Preliminary attempts at therapy with antiviral drugs and immunostimulators have been reported but are still experimental.‘,3g~4’ The average duration of illness from onset to death is about 6 to 9 months, and symptomatic care is the only therapeutic modality available. PREVENTION
Measles virus is highly contagious and is spread through respiratory droplets or through direct contact with nasal or throat secretions of infected persons. Viral excretion is seen 5 days before and 4 days after the onset of the rash and, therefore respiratory isolation is usually observed for 4 days after the onset of the rash.‘, 3,’ In immunocompromised patients, because viral excretion can be prolonged, respiratory isolation is recommended for the duration of the illness.33 g All exposed susceptible persons should be given measles vaccine within 72 hours of exposure. If the exposure time is longer or uncertain, or if there is a contraindication to vaccine use
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(immunocompromised host, anaphylaxis to egg children less than 6 ingestion, pregnancy, months of age), immune serum globulin (IG) should be used, followed 3 months later by measles vaccination (if vaccine is not contraindicated). The recommended dose of IG is 0.25 ml/kg of body weight given intramuscularly or 0.50 ml/kg of body weight given intramuscularly for immunocompromised hosts (Table 4). Several live attenuated virus vaccines are available, all capable of providing the same immunologic response as natural measles but with differences in the incidence of side effects.‘. 42,43 The vaccine virus strains presently in use in the United States (Schwarz and Moraten strains) are attenuated beyond the original Edmonston B strain, which is no longer distributed in the United States. The current vaccine is prepared in chick embryo cell culture and contains 15 kg of neomycin but no penicillin. Measles vaccine is available in monovalent form (measles vaccine), in combination with rubella (MR), and in a trivalent form combined with rubella and mumps (MMR). Measles vaccine should be kept under proper storage conditions to maintain its activity (protected from the light and at 2 to 8” C [35.6 to 46.4” F]).9 Under normal circumstances (nonepidemic), administration of the vaccine (MMR) at the age of 15 months is recommended.‘,9 After a single dose, protective concentrations of serum measles antibody are developed in 95% of vaccine recipients.” ‘, 9 Because of the large number of measles cases seen in the United States in the last 4 years, a two-dose schedule has recently been recommended by the Immunization Practices Advisory Committee (ACIP) in counties reporting more than five cases of measles among preschool-age children during each of the previous five years.14. ” In these counties, it is recommended that a first dose of monovalent measles vaccine be given at the age of 9 months or at the first visit thereafter, followed by a second dose, with MMR, at 15 months of age. This 15month dose is crucial in view of the low seroconversion rate seen in children vaccinated before the age of 12 months. This is believed to be due to the presence of circulating maternal antibodies that interfere with the infant’s immunologic response .9,‘O Because the seroconversion rate at 15 months is 95%, and because some children do not receive vaccine, the CDC has recommended revaccination of all children at the
time they enter school (at 5 to 6 years of age!.” If this routine program is impractical for certain communities, then MMR vaccine should be giver routinely at 12 months of age and a booster. should be given at 5 years. To reach those in the other problem age group, the unprotected school-age children, revaccination programs are being implemented for all persons who received their last vaccine before 1980.17 If this is not possible, then those who r-e ceived measles vaccine before the age of 15 months should be targeted. Serious complications associated with measles vaccine rarely occur.‘~ ’ J4 Localized pain and swelling may be noted and are transitory. Between 5% and 15% of the recipients may have a mild temperature elevation. Transient rashes have been reported in 5% of vaccinees, usually 5 to 7 days after vaccine administration; these are self-limited and are not contagious. Central nervous system complications, including encephalitis, have been reported in one per 3 million doses administered in the United States.“? Live measles vaccine should not be administered to pregnant women because of the theoretical risk of fetal damage.9.45 In persons with a history of severe hypersensitivity to egg or neomycin, the vaccine should be used only after skin testing. Measles vaccine should be delayed until 3 months after administration of immune globulin because of a possible interference with the active immune response. The vaccine is also contraindicated in persons with diseases or therapy associated with impaired cell-mediated immunity. These include patients with leukemia, lymphoma, or other malignant conditions and primary immunologic disorders and those undergoing therapy with steroids, antimetabolites, or radiation. Patients with human immunodeficiency virus (HIV) infection, regardless of the stage (symptomatic or asymptomatic), should receive MMR at 15 months of age, or later if not previously immunized.y,46 This recommendation is based on the lack of complications from live attenuated virus vaccines in children with HIV and the recent reports of severe complicated measles in nonimmunized persons with HIV infection. Regardless of vaccination status, persons with symptoms of HIV infection who are exposed to measles should receive immune globulin prophylaxis at the dose and by the route recommended previously. All cases of measles should be reported and
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Measles
1991
investigated promptly. The best approach to proper control of a measles outbreak is prompt vaccination or IgG administration to susceptible persons. g,17,47However, it is relevant to recognize that failure of postexposure prophylaxis with immunoglobulin or vaccine has been reported and that follow-up of these contacts is necessary.4* Isolation and prevention procedures should never be delayed until serologic confirmation of the suspected cases. All persons who cannot provide written documentation of vaccination with live measles vaccine on or after their first birthday or a physician’s confirmation of their having had measles should be promptly immunized and excluded from crowded areas (school, day-care centers). A good outbreak-control program will ultimately depend on the rapid recognition of the disease and a team approach, including physicians, nurses, social services, and community leaders, for rigorous implementation of these measures. The authors thank Ms. Joyce Bagan and Mrs. Ellen Hansen for editorial and secretarial assistance.
References 1. Marks MI. Pediatric infectious diseases. New York: Springer-Verlag, 1985:481-7. 2. Behrman RE, Vaughan VC III. Viral infections and those presumed to be caused by viruses. Measles. In: Nelson textbook of pediatrics, Philadelphia: WB Saunders, 1983:743-7. 3. Cherry JD. Measles. In: Feigin RD. Cherry JD, eds. Textbook of pediatric infectious diseases. Philadelphia: WB Saunders, 1987:1608-28. 4. Measles-United States. M M W R 1987:36:301-S. 5. Measles-United States, First 26 Weeks, 1987. M M W R 1988;37:53-7. 6. Measles-United States, 1988. M M W R 1989;38:601-5. 7. Update: Measles Outbreak-Chicago, 1989. M M W R 1990;39:317-26. 8. Sherris JC. Medical microbiology. 2nd ed. New York: Elsevier, 1990;519-23. 9. Report of the Committee on Infectious Diseases. American Academy of Pediatrics 1988:277-89. 10. Albrecht P, Ennis FA, Saltzman EJ, Krugman S. Persistence of maternal antibody in infants beyond 12 months: mechanism of measles vaccine failure. J Pediatr 1977;91: 715-8. 11. Haas EJ, Wendt VE. Atypical measles 14 years after immunization. JAMA 1976;236:1050. 12. Brodsky JL. Atypical measles. JAMA 1972;222:1415-6. 13. Cherry JD, Feigin RD, Lobes LA Jr, Shackelford PG. Atypical measles in children previously immunized with attenuated measles virus vaccines. Pediatrics 1972;50:71217. 14. Brunell PA. Measles one more time. Pediatrics 1990; 86~474-7.
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15. Measles-Dade County, Florida. M M W R 1987;36:45-8. 16. Measles-Los Angeles County, California, 1988. M M W R 1989;38:50-7. 17. Measles Prevention: Supplementary statement. M M W R 1989;38:1 l-4. 18 Tidstrom B. Complications in measles with special reference to encephalitis. Acta Med Stand 1968;184:41 l-5. 19. O ’Donovan C, Barua KN. Measles pneumonia. Am J Trop Med Hyg 1973;22:73-7. 20. Deseda JE, Spencer MJ, Cherry JD, et al. Measles antibody in healthy adults analyzed by HLA and ABO blood types. Abstract, 16th Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, October, 1976. 21. Siegel MM, Walter TK, Ablin AR. Measles pneumonia in childhood leukemia. Pediatrics 1977;60:38-40. 22. La Boccetta AC, Tornay AS. Measles encephalitis. Am J Dis Child 1964;107:247-55. 23. Johnson RT, Griffin DE, Hirsch RL, et al. Measles encephalomyelitis-clinical and immunologic studies. N Engl J Med 1984;310:137-41. 24. Jabbour JT, Duenas A, Sever JL, Krebs HM, HortaBarbosa L. Epidemiology of subacute sclerosing panencephalitis (SSPE). JAMA 1972;220:959-62. 25. Modlin JF, Jabbour JT, Witte JJ, Halsey NA. Epidemiologic studies of measles, measles vaccine, and subacute sclerosing panencephalitis. Pediatrics 1977;59: 505-12. 26. Connolly JH, Allen IV, Hurwitz LJ, Millar JHD. Measlesvirus antibody and antigen in subacute sclerosing panencephalitis. Lancet 1967;1:542-4. 77 Horta-Barbosa L, Krebs H, Ley A, Chen T-A, Gilkeson MR, Sever JL. Progressive increase in cerebrospinal fluid measles antibody levels in subacute sclerosing panencephalitis. Pediatrics 1971;47:782-3. 28. Finkel HE. Measles myocarditis. Am Heart J 1964; 671679-83. 29. Hudson JB, Weinstein L. Chang T-W. Thrombocytopenic purpura in measles. J Pediatr 1956;48:48-56. 30. Lin C-Y, Hsu H-C. Measles and acute glomerulonephritis. Pediatrics 1983;71:398-401. 3 1. Lightwood R, Nolan R. Epithelial giant cells in measles as an aid in diagnosis. J Pediatr 1970;77:59-64. 32. Hussey GD, Klein M. A randomized, controlled trial of vitamin A in children with severe measles. N Engl J Med 1990;323:160-4. 33. Barclay AJG, Foster A, Sommer A. Vitamin A supplements and mortality related to measles: a randomised clinical trial. Br Med J 1987;294:294-6. 34. Vitamin A for measles. Lancet 1987;1:1067-8. 35. Banks G, Fernandez H. Clinical use of ribavirin in measles: a summarized review. In: Smith RA, Knight V, Smith JAD, eds. Clinical applications of ribavirin. New York: Academic Press, 1980:203-9. 36. Gilbert BE, Knight V. Biochemistry and clinical applications of ribavirin. Antimicrob Agents Chemother 1986; 30:201-S. 37. Gururangan S, Stevens RF, Morris DJ. Ribavirin response in measles pneumonia. J Infect 1990;20:21921. 38. Ross LA, Kim KS, Mason WH Jr, Gomperts E. Successful treatment of disseminated measles in a patient with acquired immunodeficiency syndrome: consideration of -1.
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39.
40.
41.
42. 43.
Arguedas, Deveikis, and Marks antiviral and passive immunotherapy. A m 3 Med 1990; 88:313-4. Ogle JW, Toltzis P, Parker WD, et al. Oral ribavirin therapy for subacute sclerosing panencephalitis. J Infect Dis 1989;159:748-9. Shieh C-C, Hsieh K-H. Failure of intravenous immunoglobulin to affect the recovery of immune function after measles. Pediatr Infect Dis 3 1989;8:888-91. Jones CE, Dyken PR, Huttenlocher PR, Jabbour JT, Maxwell KW. Inosiplex therapy in subacute sclerosing panencephalitis. Lancet 1982; 1: 1034-6. Measles revaccination. Med Letter 1989;3 1:69-70. Krugman S, Giles JP, Jacobs AM, Friedman H. Studies with live attenuated measles-virus vaccine. A m J Dis Child 1962;103:183-93.
HIV
Problem Solving for Infection Instructions
Purpose: solutions
44. Landrigan RJ, Witte JJ. Neurologic disorders following live measles-virus vaccination. J A M A 1973;233:1459-02. 45. Jespersen CS, Littauer J, Sagild U. Measles as a cause $.*I fetal defects. Acta Pediatr Stand 1977;66:367-72. 46. Onorato IM, Markowitz LE, Oxtoby MJ. Childhood immunization, vaccine-preventable diseases and infcctioll with human immunodeficiency virus. Pediatr Infect Dis J 1988;6:588-95. 47. Measles-United States, First 26 Weeks, 1989: leads from the MMWR. A m J Dis Child 1990; 144:459-60. 48. Measles outbreak-Washington, 1989: Failure of delayed postexposure prophylaxis with vaccine. M M W R 1990;39. 617-9.
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Measles has become epidemic over most of the world, with an important increase in the number of cases and associated morbidity and mortality in the United States since 1986. The two major factors responsible for this rise in the number of cases are, first, the increase in unvaccinated preschool-age children and, second, vaccine nonresponders (approximately 5%). The highest attack rate occurred in teenagers (15 to 19 years old) and in nine states (82% of cases). This situation has prompted revised immunization recommendations for those counties reporting more than five cases of measles among preschool-age children during each of the previous 5 years. In these counties, a first dose with monovalent measles vaccine is recommended at 9 months of age, followed by a second dose with measles, mumps, and rubella vaccine at 15 months of age, and revaccination of all children at the time of school entry. Recent publications regarding the use of vitamin A and certain antiviral agents are encouraging and are discussed in the manuscript. All cases of measles should be reported and investigated promptly. A good outbreak-control program will depend on the rapid recognition of the disease, a team approach, and prompt vaccination or IgG administration to susceptible persons. (AM J INFECT CONTROL 1991:19:290-S)
Measles is an acute communicable disease characterized by fever, cough, coryza, conjunctivitis, an erythematous maculopapular rash, and a characteristic enanthem.‘, 2 Although clinical measles is epidemic over most of the world, its incidence was reduced in North America with the use of attenuated vaccines.3 However, an important increase in the number of cases and in associated morbidity and mortality has occurred in the United States since 1986.4-7 During the year 1989-90, 57 cases of complicated measles were admitted to Memorial Miller Children’s Hospital (0.5% of total admissions). This represented 236 in-hospital days and a total cost of $540,027. Among several factors implicated in this epidemic, the most important is that more than one third of American children are not fully immunized.4. 6*7
From the Department of Pediatrics, Division of Pediatric Infectious Diseases, Memorial Miller Children’s Hospital, Long Beach, and University of California, Irvine. Reprint requests: Adrian0 G. Arguedas, MD, Pediatric Infectious Diseases, Memorial Miller Children’s Hospital, 2801 Atlantic Ave., Long Beach, CA 90801-1428. 17/46/26263
290
ElWL@@Y
Measles virus is classified in the family of Pavarnyxoviridue, genus morbilliviruss It contains linear, negative-sense, single-stranded RNA, which codes for six virion structural proteins. The virus is very labile, inactivated by heat, ultraviolet light, lipid solvents such as ether and chloroform, and extreme degrees of acidity (pH lO). At room temperature there is a 60% loss in titers in 3 to 5 days.“, ’ Measles virus may be isolated in primary cultures of human embryonic or rhesus monkey kidney cultures. Cytopathic changes are usually visible in 5 to 10 days and consist of multinucleated giant cells with intranuclear inclusions.H CLIwloAL
AT
The clinical characteristics of the disease are different in patients with typical measles than in those with modified or atypical measles. Modified measles is defined as an infection that occurs in partially immune persons, whereas atypical measles is a clinical syndrome that occurs after exposure to natural measles in some subjects who were previously immunized with inactivated vaccine .‘, 3*’
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TYPICAL
Measles
1991
291
ILLNESS
The incubation period is approximately 10 to 15 days. The prodromal phase lasts between 1 and 3 days and is characterized by low-grade to moderate fever and respiratory symptoms that may cause the disease to be initially confused with a common cold. At this time the patient has a hacking cough, coryza, conjunctival inflammation, and photophobia. These almost always precede Koplik spots, the pathognomonic sign of measles, by 2 to 3 days. Koplik spots are grayish white dots, usually as small as grains of sand, with red areolae, that occur opposite the lower molars but may also be located irregularly over the rest of the buccal mucosa. They appear and disappear rapidly, usually within 12 to 18 hours. As they fade, there may remain red spotty discoloration of the mucosa. During the prodromal period, erythematous maculopapular lesions may be observed occasionally on the palate. At the end of the prodromal period, the posterior pharyngeal wall is usually erythematous and the patient may complain of sore throat.le3 The typical exanthem appears on about the fourteenth day after exposure, at about the peak of the respiratory symptoms and when the temperature is in the 39.5” C range. At this time the Koplik spots may have disappeared or may still be present, but these will disappear within the next 3 days. The measles exanthem first appears behind the ears and on the forehead (hairline). The spread of the rash is centrifugal from head to toe, being confluent in the face and discrete in the lower extremities (Fig. 1). Usually by the third day the rash has involved the face, neck, trunk, upper extremities, buttocks, and lower extremities. The rash is initially erythematous and maculopapular but progresses to confluence in the same manner as its spread. The exanthem begins to clear by the third to the fourth day, following the same centrifugal course of progression. As the rash fades, desquamation and a brownish discoloration occur and then disappear within 7 to 10 days.lT3 During the exanthem period, fever usually peaks by the second or third day of the rash and then falls over a Whour period. Fever that persists after the fourth day of the rash is suggestive of bacterial infection.3 Other general complaints, such as nasal discharge and conjunctivitis, also disappear by the time of defervescence. Cough usually loosens up with the appearance of the rash, but it is not uncommon for it to last 10 days or longer.‘* 3
Fig. 1. Typical measles. Note confluence per body.
of rash on up-
Pharyngitis and generalized lymphadenopathy, especially involving the cervical glands, are not uncommon findings and tend to resolve around the time the rash fades. Young children may occasionally have gastrointestinal complaints (diarrhea and vomiting), laryngitis, and croup.‘,4,5 MODIFIED
ILLNESS
Modified measles is characterized by a mild illness that usually follows the same sequence of events as typical measles. The mildness of this illness is usually due to the presence of specific measles antibodies in the affected child, either transplacentally acquired maternal antibodies in infants less than 9 months of age or antibodies produced by the administration of immune serum globulin to an exposed susceptible child. Less commonly, modified measles may be a manifestation of vaccine failure.3’ 9, lo Under these circumstances the prodromal period is shortened, with minimal cough, coryza, and low-grade fever. Koplik spots are usually ab-
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TaMe 1. Measles complications Early complications: Otitis media Laryngitis Laryngotracheitis Pneumonia Diarrhea Encephalitis Myocarditis Pericarditis Hemorrhagic measles Thrombocytopenic purpura Hepatitis Appendicitis Stevens-Johnson syndrome Late complications: Subacute sclerosing panencephalitis
sent; when they occur, they are few in number and transient. The exanthem follows the same distribution as in typical measles, but confluence is rare. Duration of illness is similar to that of the typical cases.‘, 3 ATYPICAL
IELWEEI
Atypical measles is a defined clinical entity that occurs in previously immunized persons. The majority of the reported cases are in persons who received the inactivated measles vaccine available in the United States from 1963 to 1967, but some cases also have been reported in children who received the live measles vaccine.‘, ‘l-l3 The incubation period is similar to that of typical cases (10 to 14 days), and the prodromal period is characterized by the sudden onset of high fever (40” C), headache, dry nonproductive cough, abdominal pain, and myalgia. Koplik spots are rare in atypical measles. The rash appears 2 to 3 days after the beginning of the prodromal period. Unlike typical measles, the rash first appears on the distal extremities and progresses in a cephalad direction.‘.” To date, measles virus has not been recovered from secretions of patients with atypical measles and, therefore, epidemiologic data suggest that patients with atypical measles are not contagious.3, 9 However, we believe that until further data are available, the same isolation procedures should be followed for these patients as for patients with typical measles. EPIDEYIOLOQY
Measles, a disease with worldwide distribution, is transmitted by direct contact with infec-
tious droplets or, less commonly, by airborne spread.‘, 3, 9 In the prevaccine era, measles was an epidemic disease with biennial cycles in LX-.ban areas, occurring mostly in preschooi aud young school-age children.” 3 The immunization program in the United States resulted initialiv in a 99% reduction in reported cases of measles. One third of the cases occurred in adolescents and young adults .9, I4 Since 1983, the number of measles cases reported to the Centers for Disease Control (CDC) increased annually until 1986, with a slight decrease in 1987 through 1989.” ’/ The highest attack rate (5.8 per 100,000) occurred in teenagers (15 to 19 years old) and in nine states that accounted for 82% of the total cases.” ” !I) Two major factors are responsible for this rise in the number of cases: (1) an increase in the number of unvaccinated preschool-age children, accounting for outbreaks in inner city areas, and (2) vaccine nonresponders (approximately s%f, accounting for outbreaks in highly immunized school-age populations.‘4, I7 These observations have prompted revised immunization r-ecommendations by the American Academy of Pediatrics and the CDC in an effort to raise ageappropriate immunity (see Prevention).“’ ” Epidemic measles is a winter and spring disease.3, 9 There is no gender difference, but some studies have suggested that boys are more prone to have complications, such as laryngitis, otitis media, pneumonia, and death.‘, IN,” Measles susceptibility does not vary by race, LILA, or blood type.*’ The disease is spread more commonly un-der crowded situations, as in day care centers, and morbidity and mortality are higher in immunocompromised hosts, in children under 2 years of age, and in malnourished children.3 “ ii COW’LICATIOBlS
Measles is an exanthema with high morbidity and mortality in malnourished and immunocompromised hosts. 1. 3 The chief complications of measles due to superinfection are otitis media and pneumonia (Table 1). Measles usually causes suppression of delayed hypersensitivity, leading to a transient reversal of previously positive skin testing for tuberculosis and histoplasmosis and sometimes to worsening or reactivation of mycobacterial infection.“” An exacerbation of fever (>38.5” C), change in blood count from leukopenia to leukocytosis, and development of malaise, pain, or prostration suggest a complicating bacterial infection.
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Measles 293
1991
Otitis media is the most common complication (5% to 10%) and is related to age (most common in children under 5 years).‘, 6. ’ The bacterial pathogens are similar to those seen in children without measles (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhaZis).3 Other upper respiratory tract infections, such as laryngitis, laryngotracheitis, or secondary bacterial infections of the cervical lymph nodes, are not uncommon and should be kept in mind.‘, 3 Pulmonary involvement in measles, caused by the measles virus itself, is very common.‘,3 In the majority of cases, when pneumonia is observed early in the course of the illness, measles is the cause; when this occurs farther into the disease (>3 to 4 days), secondary bacterial infection is usually implicated (Fig. 2). The roentgenographic appearance of measles viral pneumonitis is characterized by bilateral hyperinflation with diffuse infiltrates, more confluent in the hilum.‘s3 Although unilateral, segmental, and lobar pneumonias can be caused by measles virus, they are usually due to secondary bacterial pathogens,‘, 3, 2’ most commonly S. pneumoniae, H. influenzae, S. pyogenes, or Staphylococcus aureus.‘-3 Clinical manifestations of bacterial pneumonia appear late in the course of the disease and are characterized by high fever (>38.5” C), a productive cough, and progressive respiratory distress. Neurologic complications are more common in measles than in any of the other exanthems .3, 22,23 Encephalitis occurs about once in 600 to 1000 cases.3, 23 There is no correlation between the severity of measles and that of neurologic involvement or between the severity of the initial encephalitic process and the prognosis. Encephalitis usually occurs 2 days to 3 weeks after onset of the exanthem, beginning with high fever and convulsions and ending, in some cases, in coma.3, 22 It has been suggested that when encephalitis occurs early in the course of the disease, it is probably secondary to viral invasion of the central nervous system; when encephalitis occurs later, it is predominantly an immunologic phenomenon.3, 23 In most instances, examination of cerebrospinal fluid (CSF) will reveal a lymphocyte count of between 50 and 500/mm3 with an elevated protein concentration and a normal glucose CSF/serum ratio.‘,22 A normal CSF at the time of initial symptoms, however, does not rule out encephalitis and, if central nervous system
Fig. 2. Measles pneumonitis third day of infection.
in 7-month-old
infant on
(CNS) symptoms persist, should be repeated in 48 to 72 hours. The course of measles encephalitis may be brief, with recovery in about a week, or it may be prolonged and terminate in serious CNS impairment or death.3.22.23 No specific therapy is available at this time, and only supportive measures are recommended.‘, 3 Gastrointestinal complications are frequently seen in measles. In the United States from 1986 to 1989 about 4% to 17% of the patients with measles had diarrhea.4-7 In the majority of the cases this is self-limited and lasts between 5 and 7 days. Other than measles virus, no specific etiologic agent is implicated. Symptomatic therapy with close electrolyte and fluid monitoring is usually effective. In some instances, hospitalization is required because of poor fluid intake and secondary dehydration. If a bacterial pathogen is recovered (Shigella, Salmonella, or Campylobatter) from stools, specific antimicrobial therapy is recommended. Measles virus is also associated with subacute
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Table
2. Differential
diagnosis
Rubella Scarlet fever Drug rash Adenovirus infectlon Coxsackievirus infection Hemorrhagic varicella
of measles
Roseola infantum Epstein-Barr virus infectjon Kawasaki syndrome Echovirus infection Rickettsial Infection Meningococcal infection
sclerosing panencephalitis (SSPE), a progressing fatal neurologic condition seen mainly in late childhood.‘, 3, 24, 25 This complication occurs months to years after an attack of measles (1 per 100,000 infections) or, less commonly, after vaccination with live attenuated vaccine (1 per 1 ,OOO,OOOvaccinees) and causes intellectual deterioration, convulsive seizures, and motor abnormalities.3. ‘*, 24 Measles virus has been identified in brain tissue of these patients by electron microscopy, by demonstration of measles antigen through fluorescent antibody techniques, and by isolation of the agent in brain biopsy specimens. 3,23,26.*’ The mean incubation period from measles illness to onset of SSPE is 7 years, whereas for vaccinees in whom SSPE develops the mean incubation period is 3.3 years.3’ 24Boys are affected three times more commonly than girls, and in the United States SSPE is more prevalent in the southeastern part of the country and in children from farms.24 This suggests that some unknown extrinsic factors, unrelated to measles or to measles vaccine, may play an important role in the pathogenesis of this disease.3, 24 Measles has been associated with other, less common complications. Myocarditis and pericarditis occasionally occur, but clinical consequences are rare?’ Hemorrhagic measles, a severe, often fatal form of measles characterized by extensive bleeding from different organs, is rarely seen today, and little is known about its pathogenesis.3 Thrombocytopenic purpura is another bleeding disorder seen on occasion with measles, and its prognosis is usually good.3, *’ Less frequently, glomerulonephritis, StevensJohnson syndrome, hepatitis, appendicitis, ileocolitis, mesenteric lymphadenitis, and gangrene of the extremities are complications of measles .3”. 1,3 DlAt3WOSIS
The diagnosis of measles is usually made on clinical grounds and on the basis of exposure and immunization history. Laboratory confirmation
is rarely needed for typical cases but may be 01 value for the diagnosis of modified or atvpicai cases. During the prodromal stage, rnultinu. cleated giant cells can be seen in nasal mucos~~ smears and the white blood ceil count is lo\\ (2,000 to 4,000 cells/mm’) with a relative lymphocytosis (80% to 90%).‘, 3’ Measles infection can be specifically diagnosed bv virai iso lation in a tissue culture system (primary monkey kidney), by demonstration of measles antigen in exfoliated cells by the fluorescent antibody technique, by the demonstration ol hemagglutination-inhibiting test, complementfixation test, or neutralizing antibody titer increase in two sequential serum samples (3 weeks apart), or by a positive IgM measles-specific antibody during the acute phase or the first 2 weeks of the convalescent phase.‘, 1,9 For practical purposes, we recommend that in those cases in which the diagnosis cannot be made on clinical grounds serologic studies rather than viral cultures (low yield of positive results) should be pcrformed. Lumbar puncture in patients with measles encephalitis shows an increase in protein and a mild lymphocytosis with normal glucose.” In cases of subacute sclerosing panencephalitis (SSPE) the CSF will show a marked globulin elevation, predominantly IgG. In patients with SSPE, measles serum and CSF, HAI, and CF antibody titers are highly elevated (‘2 1 : 1 280).2”, ” Differential diagnosis of typical measles includes rubella, scarlet fever, drug rashes, roseola infantum, infectious mononucleosis, Kawasaki syndrome, and other viral infections (adenovirus, echovirus, and coxsackievirus infections) (Table 2).le3 Distinguishing features of rubella include its mild course, enlarged and usually tender postauricular and suboccipital nodes, normal blood count, and the usual absence of a prodromal period. Scarlet fever is usually ruled out by the presence of the Koplik spots and the typical rash seen in measles. Drug rashes may resemble the measles eruption, but a good history and the typical cephalocaudal progression of the measles rash will clarify the diagnosis. Roseola infantum is seldom seen in children over the age of 3, and it can usually be differentiated by its high initial temperature, the absence of Koplik spots, and the appearance of the rash simultaneously with defervescence. The differential diagnosis of atypical measles is similar to that of typical measles; however, the pleomorphism of the rash and the severity of
Volume 19 Number 6 December
Measles
1991
symptoms may suggest other entities, such as Rocky Mountain spotted fever, hemorrhagic varicella, drug allergy, secondary syphilis, typhus, or a meningococcal infection.‘! g A history of measles exposure and prior receipt of killed vaccine may suggest the diagnosis of atypical measles, but in the majority of cases serologic confirmation (serum HA1 + measles titers are very high) is necessary.
Table
3. Treatment
295
of measles
Symptomatic support Antimicrobials for secondary infection Consider vitamin A (Retinyl palmitate), 200,000 IU orally per day for 2 days, in malnourished children with severe measles Consider ribavirin (oral, nebulized, and/or intravenous) in patients with measles pneumonia, disseminated measles, or immunocompromised hosts (?)
TREATMENT
There is no specific treatment for uncomplicated measles (Table 3). Symptomatic support with antipyretics for high fever, bed rest, and adequate fluid intake are indicated. The patient should be protected from exposure to strong light when photophobic. Close observation for complications, such as secondary infections, is indicated. If otitis media or pneumonia develops, appropriate antimicrobial therapy should be started promptly. Such complications as encephalitis, giant cell pneumonia, and disseminated intravascular coagulation must be carefully assessed individually. Recently some studies have evaluated the value of vitamin A (400,000 IU of retinyl palmitate given orally) in children with severe measles.32-34This is based on the effect that vitamin A has on the maintenance of normal epithelial tissues and the fact that measles infects and damages the epithelium throughout the body, resulting in increased morbidity and mortality from respiratory and diarrhea1 causes. Although the idea seems very attractive, we believe that until this observation is confirmed, we could not recommend the routine use of vitamin A in wellnourished children. However, the benefits may outweigh the risks in a malnourished child with severe measles, and 200,000 IU of retinyl palmitate should be given orally for 2 days in an attempt to reduce morbidity and mortality. Although no specific antiviral therapy against measles is available, ribavirin (l-beta-Dribofuranosyl1,2,4 triazole-3-carboxamide) has shown in vitro and clinical activity against measles virus.35-36 Reports of patients with measles pneumonia, 37 disseminated measles,38 and SSPE3’ treated with ribavirin indicate that this drug may be considered in these situations, especially in immunocompromised hosts. More clinical trials are necessary before firm recommendations can be made. Immunoglobulin has no established benefit in the therapy of measles. A recent controlled clin-
Table
4. Prevention
of measles
Sltuatlon
Recommendation
Exposed susceptible person (~72 hr) Exposed susceptible person (>72 hr) or Contraindication for vaccine use *IgG dose for immunocompromised
Measles vaccine IgG 0.25 ml/kg IM*
host: 0.50 ml/kg IM.
ical trial in immunocompetent hosts failed to document any effect of the administration of intravenous immunoglobulin on the clinical course or the immune function recovery during the acute phase of the disease.40 In a single AIDS patient, however, the combined administration of intravenous IgG (400 mg/kg daily for 5 days) with ribavirin therapy was beneficial, and such treatment might be considered under these circumstances.38 At present there is no specific therapy for SSPE. Preliminary attempts at therapy with antiviral drugs and immunostimulators have been reported but are still experimental.‘,3g~4’ The average duration of illness from onset to death is about 6 to 9 months, and symptomatic care is the only therapeutic modality available. PREVENTION
Measles virus is highly contagious and is spread through respiratory droplets or through direct contact with nasal or throat secretions of infected persons. Viral excretion is seen 5 days before and 4 days after the onset of the rash and, therefore respiratory isolation is usually observed for 4 days after the onset of the rash.‘, 3,’ In immunocompromised patients, because viral excretion can be prolonged, respiratory isolation is recommended for the duration of the illness.33 g All exposed susceptible persons should be given measles vaccine within 72 hours of exposure. If the exposure time is longer or uncertain, or if there is a contraindication to vaccine use
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(immunocompromised host, anaphylaxis to egg children less than 6 ingestion, pregnancy, months of age), immune serum globulin (IG) should be used, followed 3 months later by measles vaccination (if vaccine is not contraindicated). The recommended dose of IG is 0.25 ml/kg of body weight given intramuscularly or 0.50 ml/kg of body weight given intramuscularly for immunocompromised hosts (Table 4). Several live attenuated virus vaccines are available, all capable of providing the same immunologic response as natural measles but with differences in the incidence of side effects.‘. 42,43 The vaccine virus strains presently in use in the United States (Schwarz and Moraten strains) are attenuated beyond the original Edmonston B strain, which is no longer distributed in the United States. The current vaccine is prepared in chick embryo cell culture and contains 15 kg of neomycin but no penicillin. Measles vaccine is available in monovalent form (measles vaccine), in combination with rubella (MR), and in a trivalent form combined with rubella and mumps (MMR). Measles vaccine should be kept under proper storage conditions to maintain its activity (protected from the light and at 2 to 8” C [35.6 to 46.4” F]).9 Under normal circumstances (nonepidemic), administration of the vaccine (MMR) at the age of 15 months is recommended.‘,9 After a single dose, protective concentrations of serum measles antibody are developed in 95% of vaccine recipients.” ‘, 9 Because of the large number of measles cases seen in the United States in the last 4 years, a two-dose schedule has recently been recommended by the Immunization Practices Advisory Committee (ACIP) in counties reporting more than five cases of measles among preschool-age children during each of the previous five years.14. ” In these counties, it is recommended that a first dose of monovalent measles vaccine be given at the age of 9 months or at the first visit thereafter, followed by a second dose, with MMR, at 15 months of age. This 15month dose is crucial in view of the low seroconversion rate seen in children vaccinated before the age of 12 months. This is believed to be due to the presence of circulating maternal antibodies that interfere with the infant’s immunologic response .9,‘O Because the seroconversion rate at 15 months is 95%, and because some children do not receive vaccine, the CDC has recommended revaccination of all children at the
time they enter school (at 5 to 6 years of age!.” If this routine program is impractical for certain communities, then MMR vaccine should be giver routinely at 12 months of age and a booster. should be given at 5 years. To reach those in the other problem age group, the unprotected school-age children, revaccination programs are being implemented for all persons who received their last vaccine before 1980.17 If this is not possible, then those who r-e ceived measles vaccine before the age of 15 months should be targeted. Serious complications associated with measles vaccine rarely occur.‘~ ’ J4 Localized pain and swelling may be noted and are transitory. Between 5% and 15% of the recipients may have a mild temperature elevation. Transient rashes have been reported in 5% of vaccinees, usually 5 to 7 days after vaccine administration; these are self-limited and are not contagious. Central nervous system complications, including encephalitis, have been reported in one per 3 million doses administered in the United States.“? Live measles vaccine should not be administered to pregnant women because of the theoretical risk of fetal damage.9.45 In persons with a history of severe hypersensitivity to egg or neomycin, the vaccine should be used only after skin testing. Measles vaccine should be delayed until 3 months after administration of immune globulin because of a possible interference with the active immune response. The vaccine is also contraindicated in persons with diseases or therapy associated with impaired cell-mediated immunity. These include patients with leukemia, lymphoma, or other malignant conditions and primary immunologic disorders and those undergoing therapy with steroids, antimetabolites, or radiation. Patients with human immunodeficiency virus (HIV) infection, regardless of the stage (symptomatic or asymptomatic), should receive MMR at 15 months of age, or later if not previously immunized.y,46 This recommendation is based on the lack of complications from live attenuated virus vaccines in children with HIV and the recent reports of severe complicated measles in nonimmunized persons with HIV infection. Regardless of vaccination status, persons with symptoms of HIV infection who are exposed to measles should receive immune globulin prophylaxis at the dose and by the route recommended previously. All cases of measles should be reported and
Volume 19 Number 6 December
Measles
1991
investigated promptly. The best approach to proper control of a measles outbreak is prompt vaccination or IgG administration to susceptible persons. g,17,47However, it is relevant to recognize that failure of postexposure prophylaxis with immunoglobulin or vaccine has been reported and that follow-up of these contacts is necessary.4* Isolation and prevention procedures should never be delayed until serologic confirmation of the suspected cases. All persons who cannot provide written documentation of vaccination with live measles vaccine on or after their first birthday or a physician’s confirmation of their having had measles should be promptly immunized and excluded from crowded areas (school, day-care centers). A good outbreak-control program will ultimately depend on the rapid recognition of the disease and a team approach, including physicians, nurses, social services, and community leaders, for rigorous implementation of these measures. The authors thank Ms. Joyce Bagan and Mrs. Ellen Hansen for editorial and secretarial assistance.
References 1. Marks MI. Pediatric infectious diseases. New York: Springer-Verlag, 1985:481-7. 2. Behrman RE, Vaughan VC III. Viral infections and those presumed to be caused by viruses. Measles. In: Nelson textbook of pediatrics, Philadelphia: WB Saunders, 1983:743-7. 3. Cherry JD. Measles. In: Feigin RD. Cherry JD, eds. Textbook of pediatric infectious diseases. Philadelphia: WB Saunders, 1987:1608-28. 4. Measles-United States. M M W R 1987:36:301-S. 5. Measles-United States, First 26 Weeks, 1987. M M W R 1988;37:53-7. 6. Measles-United States, 1988. M M W R 1989;38:601-5. 7. Update: Measles Outbreak-Chicago, 1989. M M W R 1990;39:317-26. 8. Sherris JC. Medical microbiology. 2nd ed. New York: Elsevier, 1990;519-23. 9. Report of the Committee on Infectious Diseases. American Academy of Pediatrics 1988:277-89. 10. Albrecht P, Ennis FA, Saltzman EJ, Krugman S. Persistence of maternal antibody in infants beyond 12 months: mechanism of measles vaccine failure. J Pediatr 1977;91: 715-8. 11. Haas EJ, Wendt VE. Atypical measles 14 years after immunization. JAMA 1976;236:1050. 12. Brodsky JL. Atypical measles. JAMA 1972;222:1415-6. 13. Cherry JD, Feigin RD, Lobes LA Jr, Shackelford PG. Atypical measles in children previously immunized with attenuated measles virus vaccines. Pediatrics 1972;50:71217. 14. Brunell PA. Measles one more time. Pediatrics 1990; 86~474-7.
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15. Measles-Dade County, Florida. M M W R 1987;36:45-8. 16. Measles-Los Angeles County, California, 1988. M M W R 1989;38:50-7. 17. Measles Prevention: Supplementary statement. M M W R 1989;38:1 l-4. 18 Tidstrom B. Complications in measles with special reference to encephalitis. Acta Med Stand 1968;184:41 l-5. 19. O ’Donovan C, Barua KN. Measles pneumonia. Am J Trop Med Hyg 1973;22:73-7. 20. Deseda JE, Spencer MJ, Cherry JD, et al. Measles antibody in healthy adults analyzed by HLA and ABO blood types. Abstract, 16th Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, October, 1976. 21. Siegel MM, Walter TK, Ablin AR. Measles pneumonia in childhood leukemia. Pediatrics 1977;60:38-40. 22. La Boccetta AC, Tornay AS. Measles encephalitis. Am J Dis Child 1964;107:247-55. 23. Johnson RT, Griffin DE, Hirsch RL, et al. Measles encephalomyelitis-clinical and immunologic studies. N Engl J Med 1984;310:137-41. 24. Jabbour JT, Duenas A, Sever JL, Krebs HM, HortaBarbosa L. Epidemiology of subacute sclerosing panencephalitis (SSPE). JAMA 1972;220:959-62. 25. Modlin JF, Jabbour JT, Witte JJ, Halsey NA. Epidemiologic studies of measles, measles vaccine, and subacute sclerosing panencephalitis. Pediatrics 1977;59: 505-12. 26. Connolly JH, Allen IV, Hurwitz LJ, Millar JHD. Measlesvirus antibody and antigen in subacute sclerosing panencephalitis. Lancet 1967;1:542-4. 77 Horta-Barbosa L, Krebs H, Ley A, Chen T-A, Gilkeson MR, Sever JL. Progressive increase in cerebrospinal fluid measles antibody levels in subacute sclerosing panencephalitis. Pediatrics 1971;47:782-3. 28. Finkel HE. Measles myocarditis. Am Heart J 1964; 671679-83. 29. Hudson JB, Weinstein L. Chang T-W. Thrombocytopenic purpura in measles. J Pediatr 1956;48:48-56. 30. Lin C-Y, Hsu H-C. Measles and acute glomerulonephritis. Pediatrics 1983;71:398-401. 3 1. Lightwood R, Nolan R. Epithelial giant cells in measles as an aid in diagnosis. J Pediatr 1970;77:59-64. 32. Hussey GD, Klein M. A randomized, controlled trial of vitamin A in children with severe measles. N Engl J Med 1990;323:160-4. 33. Barclay AJG, Foster A, Sommer A. Vitamin A supplements and mortality related to measles: a randomised clinical trial. Br Med J 1987;294:294-6. 34. Vitamin A for measles. Lancet 1987;1:1067-8. 35. Banks G, Fernandez H. Clinical use of ribavirin in measles: a summarized review. In: Smith RA, Knight V, Smith JAD, eds. Clinical applications of ribavirin. New York: Academic Press, 1980:203-9. 36. Gilbert BE, Knight V. Biochemistry and clinical applications of ribavirin. Antimicrob Agents Chemother 1986; 30:201-S. 37. Gururangan S, Stevens RF, Morris DJ. Ribavirin response in measles pneumonia. J Infect 1990;20:21921. 38. Ross LA, Kim KS, Mason WH Jr, Gomperts E. Successful treatment of disseminated measles in a patient with acquired immunodeficiency syndrome: consideration of -1.
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HIV
Problem Solving for Infection Instructions
Purpose: solutions
44. Landrigan RJ, Witte JJ. Neurologic disorders following live measles-virus vaccination. J A M A 1973;233:1459-02. 45. Jespersen CS, Littauer J, Sagild U. Measles as a cause $.*I fetal defects. Acta Pediatr Stand 1977;66:367-72. 46. Onorato IM, Markowitz LE, Oxtoby MJ. Childhood immunization, vaccine-preventable diseases and infcctioll with human immunodeficiency virus. Pediatr Infect Dis J 1988;6:588-95. 47. Measles-United States, First 26 Weeks, 1989: leads from the MMWR. A m J Dis Child 1990; 144:459-60. 48. Measles outbreak-Washington, 1989: Failure of delayed postexposure prophylaxis with vaccine. M M W R 1990;39. 617-9.
To identify problems for these problems
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Control
for Authors
to HIV and infection
control
as well as suggest
Preparation of manuscripts: Be brief! Ideally, each piece should be 2 JOURNALpages or less including references (2 JOURNALpages = 6 double-spaced typewritten pages). References: Include no more than 10 references. Past topics: Universal precautions, HIV testing in health care workers, the hospital HIV coordinator
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health care worker, prophylactic treatment after workplace exposure, infection control and home care for HIV, infection control and pediatric HIV, HIV testing of hospital patients For more information, Bill Valenti, MD Associate Editor
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