Rosalie Sagraves, Pharm D Professor of Pharmacy Practice College of Pharmacy Adjunct Associate Professor of Pediatrics College of Medicine University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma
Childhood Immunization . Part I . Cathy
Y. Poon,
T
he prevention of infectious diseases through worldwide immunization programs has reduced the incidence of serious contagious childhood illnesses. The benefits of immunization range from partial to complete protection against such diseases. However, immunization is not without risks. Risks range from mild to severe life-threatening side effects. Thus recommendations for immunization from the Committee on Infectious Diseasesof the American Academy of Pediatrics (AAP) and the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control (CDC) are made based on evidence of benefits, cost, and risks of adverse reactions to achieve optimal protection against certain infectious diseases. With the introduction of new products and the recognition of disease outbreaks, changes in vaccination recommendations occur frequently. Some recent changes include the administration of two doses instead of one dose of measles-mumps-rubella (MMR) vaccine, development of acellular pertussis vaccines, introduction of new Hemophilw b conjugate vaccines, and new recommendations for hepatitis B immunization. In a two-part series, the epidemiology, pathophysiology, and clinical manifestations of several preventable infectious diseases will be reviewed. Diphtheria, tetanus, pertussis, measles, mumps, rubella, and the vaccines used to prevent these illnesses will be discussed in Part I. . DIPHTHERIA, Diphtheria
TETANUS, AND PERTUSSIS
Diphtheria is caused by Cwynebacterium diphtheria. In 1921, more than 200,000 cases, primarily in children,
At the time of writing this paper, Dr. Cathy Y. Poon was a Clinical Instructor and a Postdoctoral Pediatric Pharmacotherapy Resident at the College of Pharmacy, the University of Oklahoma Health Sciences Center and Department of Pharmacy, Children’s Hospital of Oklahoma, Oklahoma City, Oklahoma.
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were reported (CDC, 1991a), but today diphtheria is a rare disease in the United States because of vaccination programs. Approximately 97% of children in the United States are given at least three doses of diphtheria-tetanus-pertussis (DTP) vaccine before entering school (CDC, 1991a). Diphtheria is an acute infection of the skin or upper respiratory tract. Typically, C. diphtheria contaminates the skin at the site of a wound. The toxin elaborated by the microorganism then causes inflammation and destruction of the epithelium. A grey pseudomembrane is usually formed over the tonsils, larynx, and pharynx. The toxin often spreads to the heart, liver, kidneys, adrenal glands, and nervous system where damage may occur. Vaccination generally provides only 3 years of full immunity and 10 years of partial immunity (Frenkel, 1990). For the prevention of this disease, diphtheria toxoid is usually administered in combination with pertussis vaccine and tetanus toxoid (Table 1). Tetanus
Since the routine use of tetanus toxoid was instituted, tetanus cases in the United States declined from 560 in 1947 to 64 in 1990 (CDC, 1991b). The number of cases over the last decade has remained relatively constant, averaging about 70 cases per year (CDC, 1991b). Presently, tetanus is primarily a disease of older adults with two thirds of reported cases occurring in individuals 50 years of age or older (CDC, 1991a). Like diphtheria and pertussis, tetanus occurs exclusively among persons who are inadequately vaccinated or in infants whose umbilical stumps are contaminated with Costridium tetani. For infants born to mothers with appropriate immunization, protective immunity is conferred to the infant from the transplacental transfer of maternal antibodies. Fortunately, with improved prevention strategies, neonatal tetanus has declined. Two-thirds of tetanus cases follow minor puncture JOURNAL
OF PEDIATRIC
HEALTH
CARE
Journal
of
Pediatric
n
Health
TABLE
1
Pediatric
Care
Recommended
RECOM4iMW
schedule
for routine
AGE
Newborn 2 Months
4 Months
6 Months
HBV DTP OPV HbCV HBV DTP OPV HhCV DTP OPV HbCV HBV HbCV booster
MMR
HbCV booster
18 Months
DTP
OPV 4-6 Years (at or before entry to kindergarten or elementary school) 14-16 Years
DTP OPV MMR Td
371
of infants and children
VACCINES
12 Months
15 Months
immunization
Pharmacology
COMMEMTS
First dose of HBV is administered before hospital discharge. DTP may be given as eariy as 6 weeks of age, then at 4-S week intervals for the first three doses
-
HbCV may be given either as HbOC or PRP-OMP Second dose of HBV may be given between 1-2 months HbCV may be given either as HbOC or PRP-OMP
Optional dose of OPV, but recommended in high-risk areas If HbOC was used, recommend another dose at 6 months Third dose of HBV may be given between 6-18 months If PRP-OMP was used previously, recommend a HbCV booster dose given at 12 months as the third dose of PRP-OMP MMR is usually not given to infants younger than 15 months of age but may be given at 12 months in high-’ risk areas If HbOC was used previously, recommend another HbCV booster at 15 months, that may be given as PRP-OMP, PRP-D,or HbOC DTP may be given between 15-18 months, but usually between 6 and 12 months after the third dose, and may be given simultaneously with MMR at 15 months OPV may be given simultaneously with MMR and HbCV at 15 months or any time between 12 and 24 months DTP can be given up to seventh birthday
AAP recommends the administration of the second dose of MMR at 1 l-1 2 years of age Repeat every 10 years throughout life
Adapted from AAP, 1989; AAP, 1991; AAP, 1992; CDC, 1982; CDC, 1989a; CDC, 1989b; CDC, 1990; & CDC, 1991a. HBV, Hepatitis B virus vaccine (refer to Childhood immunization, Part II, for details); DTP, diphtheria toxoid, tetanus toxoid, whole-cell pertussis vaccine; OPV, oral poliovirus vaccine; HbCV, Hemophilus b conjugate vaccine (three preparations are available [refer to Childhood Immunization, Part II, for details]: PRP-D [ProHIBiTI, polyribosylribitoi phosphate conjugated to diphtheria toxoid; HbOC [HibTITERI, polyribosylribitoi phosphate oligosaccharide conjugated with a nontoxic mutant diphtheria toxin; PRP-OMP [PedvaxHIB], polyribosylribitol phosphate conjugated with an outer membrane protein of N. meningitidis); MMR, measles, mumps, rubella vaccine;Td, tetanus toxoid (full dose) and adult strength diphtheria toxoid.
wounds of the hands or feet. C. tetani produces a neu-
Pertussis
rotoxin, tetanospasmin, that causes severe muscle spasms. The onset of tetanus occurs gradually over 1 to 7 days after the puncture wound. UsuaIly, severe spasms of the jaw (lockjaw) are noted within 48 hours, followed by stiffhess of the neck, back, and abdominal muscles. Severe illness may result in swallowing difficulties and seizures. Severe spasms usually persist for 1 or more weeks and then gradually subside over several weeks. Tetanus toxoid contains antigens that induce protective concentrations of serum antitoxins that provide adequate protection against tetanus for approximately 10 years. Secondary immunization or boosters are required every 10 years after the primary immunization series to maintain appropriate antitoxin levels for individuals of all ages (Table 1). DTP is preferred by the AAP and ACIP for childhood tetanus immunization.
Pertussis or whooping cough was once a major cause of infant and childhood morbidity and death in the United States. In 1934 at the peak incidence of pertussis disease, 265,269 cases were reported, with 1,718 deaths (CDC, 1991a). With the introduction of pertussis vaccine, reported cases declined to 1,730 cases in 1980 (CDC, 1991a). Because of negative publicity surrounding adverse reactions associated with pertussis vaccine (Kulenkampff, Schwartzman, &Wilson, 1974)) vaccine use declined dramatically over the last decade. This has lead to a steady increase in the incidence of pertussis from 1,248 cases in 1980 to 4,570 in 1990, with an average of eight deaths per year (CDC, 1991b). Pertussis is caused by a small fastidious gram-negative bacillus Bordetella pertush. Pertussis is a highly contagious respiratory tract infection that causes a 90% in-
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Pharmacology
fection rate in household contacts of index cases (Frenkel, 1990). Pertussis is most severe in young children and may cause pneumonia, seizures, and encephalopathy. Infection may present with severe bronchitis, rhinitis, sneezing, and coughing. The cough may become paroxysmal with 10 to 30 coughs ending in a loud inspiratory “whoop,” hence the term whooping wu~~. The first pertussis vaccine was developed in 1925. In the late 194Os, standardized whole-cell pertussis vaccines combined with diphtheria and tetanus toxoid were developed and are still used today (Table 2). Because of adverse reactions reported for pertussis vaccine (Cody, Baraff, Cherry, Marcy, & Manclark, 198 1; Long et al., 1990), recent efforts have focused on developing safer, effective pertussis vaccines. Acellular pertussis vaccines have been developed that provide protective immunity with potentially fewer adverse reactions. Recently, a diphtheria, tetanus toxoid, and acellular pertussis vaccine (DTaP) was licensed as Acel-Imune (Lederle Laboratories, Pearl River, N. Y .) in the United States. This vaccine is recommended only for the fourth and fifth doses of DTP vaccination, and it is not licensed for the first three dose series regardless of age (CDC, 1992). Pichichero et al. (1992) recently evaluated the immunogenicity of and adverse reactions to another DTaP preparation in young children who were given the product for primary immunization. This acellular vaccine was compared to whole-cell pertussis vaccine in 388 infants. The investigators concluded that this DTaP vaccine when given as a primary series produced greater immunogenicity and fewer adverse reactions than whole-cell DTP (Pichichero et al., 1992). However, based on experiences in Sweden and Japan with acellular pertussis vaccines, effective protective immunity is questionable when the vaccine is administered during early infancy. Therefore whole-cell pertussis vaccine is recommended for primary immunization in infants until further studies show equivalent or superior efficacy and safety with DTaP. The incidence of adverse reactions to whole-cell pertussis vaccines has been assessed in several large studies (Barkin & Pichichero, 1979; Cody et al., 1981; Rutledge & Snead, 1986; Shields et al., 1988; Walker, Jick, Perera, Knauss & Thompson, 1988). The vaccine has been associated with relatively mild, local and severe, systemic reactions. Some local reactions include redness, tenderness, and swelling. Fever, crying, and irritability are often noted. These are common, nonspecific side effects that are generally seen within 12 to 24 hours after vaccination. Serious, uncommon reactions include persistent, high-pitched crying; convulsions, frequently associated with fever; and hypotonic responses. The most severe reaction reported with whole-cell pertussis vaccine administration is encephalopathy resulting in
permanent brain damage or death (Brody & Sorley, 1947; Byers & Moll, 1948). To date, whole-cell pertussis vaccine has not been statistically linked to encephalopathy, neurologic damage, or death (Edwards & Karzon, 1990). A recent report by the Institute of Medicine (Howson & Fineberg, 1992) addresses the controversies surrounding the safety of whole-cell pertussis vaccine. The Institute concluded that the evidence reviewed is consistent with a causal relation between DTP vaccine and acute encephalopathy. Presently, the general consensus held by many clinicians is that the pertussis vaccine helps unmask underlying central nervous system manifestations, but the vaccine does not directly engender an encephalopathic state (Dyer, 1988; Shields et al., 1988; Walker et al., 1988). DTP Vaccine
Diphtheria and tetanus toxoids and pertussis vaccine are available as single antigen or in various combinations (Table 2). DTP is the preparation recommended by the AAP and ACIP, unless otherwise contraindicated. The diphtheria and tetanus toxoid (Td) preparation is recommended for individuals older than 7 years of age. It contains one-eighth to one-tenth of the diphtheria dose found in DTP or DT (diphtheria and tetanus toxoid preparation for pediatric use) because side effects are more likely and generally are more severe in older children and adults. Additionally, boosting of immunity in older children and adults may be elicited with smaller toxoid doses (Frenkel, 1990). If a combination product is contraindicated, single-antigen products are recommended. The administration of a preparation that contains pertussis vaccine should be done cautiously because it is usually the pertussis component that is responsible for most serious adverse reactions. Absolute contraindications for further DTP vaccination include the experiencing of an immediate anaphylactic reaction or encephalopathy that occurs within 7 days after DTP vaccination. The occurrence of any of the following adverse effects within 48 hours after vaccination should be a precaution or warning that further vaccinating should be done only when benefits outweigh risks: a temperature of 40.5” C (105“ F) or more of unknown cause; collapse or shock-like state (hypotonic-hyporesponsive episode); and persistent, inconsolable crying lasting 3 hours or more. Also listed as a precaution to vaccination is the development of convulsions, with or without fever, within 3 days after vaccination (CDC, 1991a). Infants and young children who have a history of seizures are at an increased risk of seizures after DTP (Livengood, Mullen, White, Brink, & Orenstein, 1989). The only contraindication to the administration of diphtheria toxoid or tetanus toxoid is a history of a
Journal of Pediatric Health
Pediatric
Care
TABLE 2 Vaccines and toxoids and rubella
n
GENERIC
available
Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) Diphtheria and tetanus toxoids, adsorbed (TD) (for pediatric use only)
Diphtheria and tetanus toxoids, adsorbed (Td) (for adult use only)
Tetanus toxoid,
adsorbed
Tetanus toxoid,
fluid
Measles, mumps, and rubella virus vaccine, live (MMR) Measles (rubeola) virus vaccine, live, attenuated (M) Mumps virus vaccine, live Rubella virus vaccine,
live (R)
Measles (rubeola) and rubella virus vaccine, live (MR) Rubella and mumps virus vaccine, live Adapted from companies.
States as diphtheria,
MANUFACTURER (TRADE NAME)
NAME
Diphtheria and tetanus toxoids and pertussis vaccine, adsorbed (D-W
in the United
Pharmacology
373
tetanus, pertussis, measles, mumps, STORAGE REQUIREMENTS
DOSE
Connaught Laboratories, Inc. Lederle Laboratories (TriImmunol) Lederle Laboratories (Acel-lmune) Connaught Laboratories, Inc. Lederle Laboratories Sclavo, Inc. Wyeth-Ayerst Laboratories Connaught Laboratories, Inc. Lederle Laboratories Sclavo, Inc. Wyeth-Ayerst Laboratories Connaught Laboratories, Inc. Lederle Laboratories Sclavo, Inc. Wyeth-Ayerst Laboratories Connaught Laboratories, Inc. Wyeth-Ayerst Laboratories Merck, Sharp & Dohme (M-M-R II) Merck, Sharp & Dohme (Attenuvax) Merck, Sharp & Dohme (Mumpsvax) Merck, Sharp & Dohme (Meruvax II) Merck, Sharp & Dohme (M-R-Vax II) Merck, Sharp & Dohme (Biavax)
Boyd, J.R. (Ed.). Facts and comparisons
(pp. 460-463,
468a-471
neurologic or severe hypersensitivity reaction after a previous dose of either toxoid. Although pregnancy is not a contraindication for diphtheria or tetanus immunization, the recommendation is to delay administration of Td until the second trimester to minimize any potential for teratogenic reactions (CDC, 1991a). DTP is recommended by the ACIP and AAP for primary immunization against diphtheria, tetanus, and pertussis. For children 6 weeks through 6 years of age, primary immunization includes four doses of the DTP vaccine (Table 1). If pertussis vaccine is contraindicated,
0.5 ml intramuscularly
Store at 2” to 8” C; do not freeze.
1
0.5 ml intramuscularly cutaneously
or sub-
Before and after reconstitution, store at 2” to 8” C; protect from light; reconstitute before use; discard if not used within 8 hours.
0.5 ml subcutaneously
b, & 852).
St. Louis: 1.8. Lippincott.
Verified
by author
communication
with all
DT should be administered instead of DTP. For children who have not received any DTP immunizations by 1 year of age, an alternate schedule is recommended (American Academy of Pediatrics, 1991; CDC, 1991a). A DTP booster should be administered before school enrollment, between 4 and 6 years of age. Subsequent booster injections, given as Td, are recommended at lo-year intervals throughout life beginning at age 14 to 16 years, or 10 years after the last DTP dose (Table 1). A child born under unhygienic conditions to a
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Volume 6, Number 6 November-December 1992
Pharmacology
woman who has not been vaccinated against tetanus is at risk for neonatal tetanus. To provide some protection for such an infant, the mother should be given two doses of Td 4 to 8 weeks apart during the last trimester before delivery (CDC, 199 la). n MEASLES, MUMPS, AND RUBELLA Measles (Rubeola)
Measles was once the most common vaccine-preventable cause of death among children worldwide, with an estimated 2.5 million deaths occurring annually during the early 1980s (Markowitz & Orenstein, 1990). Secondary to worldwide immunization efforts, measles has become a rare disease in many countries. However, outbreaks continue to occur, particularly in two susceptible groups: unvaccinated preschool-aged children and in previously vaccinated individuals secondary to vaccine failure. In the United States, reported measles cases increased almost sixfold from 1988 to 1989. The number of cases then increased another 50% in the next year to 27,786 cases (CDC, 1991b). Failure to eliminate or prevent measles has lead to new recommendations for measles vaccination. A second dose of measles vaccine was recommended by the ACIP and AAP in 1989. Measles is an acute, highly contagious systemic infection, which most commonly affects preschool-aged children. The primary infection site is the respiratory epithelium of the nasopharynx. Measles is considered communicable from 1 to 2 days before and for 4 days after the onset of rash. During this period, measles may be transmitted by direct contact. After an incubation period, a prodrome consisting of fever and malaise typically develops. Then cough, coryza, and conjunctivitis follow. Koplik? spots, a pathognomonic enanthema, are characterized by small bluish-white spots on the buccal mucosa that can be noted during the prodrome period. A characteristic rash usually appears 2 to 4 days after the onset of prodromal symptoms. The rash generally starts on the face, then spreads to the trunk and extremities. Initially, it is a maculopapular rash, but over the next week the rash gradually becomes confluent and slowly fades. Several measles vaccines were developed in the 1960s. The Enders’ attenuated Edmonston strain measles vaccine, which is found in the trivalent MMR vaccine commonly used today (Table 2), induced both humoral and cellular immune responses. The efficacy for this vaccine used in the United States is more than 95% when administered to children after 12 months of age (Davis et al., 1987). Primary vaccination failure is directly related to seroconversion rates after vaccine administration and appears to be age dependent. Epidemiologic studies have shown a higher attack rate for measles among persons vaccinated before 12 months of age compared to those vaccinated at 15 months of age
or older (Orenstein et al., 1986). This may occur because maternal antibodies may persist beyond 12 months of age; an adequate immune response may not be mounted when an infant is vaccinated too early (Albrecht, Ennis, Saltzman, & Krugman, 1977). Lifelong immunity is usually conferred with one disease exposure; however, measles vaccination does not guarantee lifelong immunity. Mumps
Mumps is a communicable disease of children and young adults that may affect most organs in the body, but 30% to 40% of those who contract mumps are asymptomatic. Mumps is most common in children between the ages of 5 and 9 years, but the disease is generally more severe in older children and adults. One episode of the disease, clinical or subclinical, generally provides lifelong immunity. After the introduction of mumps vaccine in the United States, reported cases of mumps have declined dramatically to a low of 2,982 cases in 1985. In 1987, a fivefold increase in reported cases occurred, but since then, the number of cases has decreased to approximately 5,000 between 1988 and 1990 (CDC, 1991b). Infection occurs through direct respiratory contact. Once infected, the virus replicates in the nasopharyngeal mucosa and lymph node regions and presumably causes a primary viremia. This may lead to viral seeding of various organs. Parotid involvement is the most common and distinctive manifestation of mumps. Central nervous system involvement may present as headache, mental confusion, stiff neck, and cerebral spinal fluid abnormalities. Mumps infection during the first trimester of pregnancy can increase the risk of spontaneous abortion; however, once the virus crossesthe placenta, no evidence exists that it causes congenital malformations. Live, attenuated mumps vaccine was licensed in 1967 and was recommended for routine use in 1977. Efficacy rates are between 75% and 91% (Sullivan, Halpin, Marks, & Kim-Farley, 1985; Wharton, Cochi, Hutcheson, Bistowish, & Schaffher, 1988). Evidence supports that protective immunity persists for 20 years after vaccination. Mumps vaccination is effective when administered any time after the disappearance of passively acquired maternal antibody, usually about 1 year of age. Mumps vaccine is usually given as part of the trivalent preparation, MMR (Table 1). Rubella (German Measles)
In the prevaccination era, rubella was a common childhood disease. Most cases occurred in children between the ages of 5 and 9 years. Since the introduction of rubella vaccine in 1969, rubella caseshave declined from 57,686 to 1,125 in 1990. Rubella is acquired through droplet contact from nasopharyngeal secretions. Viral
Journal of Pediatric Health Care
replication takes place in the nasopharyngeal mucosa and causes a transient viremia. Postnatal rubella is generally mild and self-limiting. The most common manifestations include transient erythematous rash (sometimes pruritis), low-grade fever, arthralgia, and lymphadenopathy. The most significant consequences of rubella are miscarriages, stillbirths, fetal anomalies, and abortions that result from rubella infection during pregnancy, especially in the first trimester. Because of the serious fetal effects, immunization programs have been targeted at women of childbearing age before pregnancy to prevent or eliminate congenital rubella syndrome (CRS) . CRS is a severe, disseminated, and chronic form of rubella that may affect every organ system. The most common anomalies associated with CRS are auditory, ophthalmic, cardiac, and neurologic. Rubella vaccine is available in combination with measles and/or mumps or as monovalent preparation (Table 2). The live rubella-virus vaccine currently distributed in the United States is prepared in human diploid cell cultures, RA 27/3. The present vaccine is more immunogenic, provides a greater resistance to reinfection, and has lower reaction rates than older products. After proper vaccination, protection against clinical rubella and viremia for at least 15 years develops in about 90% of those being vaccinated (Greaves, Orenstein, Hinman, & Nersesian, 1983). MMR
Vaccine
The most commonly administered vaccine for measles, mumps, and rubella is the trivalent preparation, MMR. Combinations and single-antigen preparations that contain live, attenuated antigens are available for MMR (Table 2). The AAP and ACIP recommend the administration of MMR vaccine for immunization in all susceptible individuals, unless one or more of the components are contraindicated. Two doses are recommended, with the first dose administered at 15 months of age, except for children in high-risk areas who should receive the first dose at 12 months of age. Both Cornmittees agree that a second MMR immunization should be administered to insure immunity and avoid vaccine failure. The ACE’ recommends that the second dose be administered between 4 and 6 years of age or before grade school entry. By receiving this MMR dose at the same time as DTP, the need to make an additional visit to a health care provider is eliminated, the risk of noncompliance or poor follow-up decreases. The AAI’ recommends that the second MMR dose be administered at age 11 to 12 years because documentation has shown that most measles and/or rubella vaccination failures occur between 10 and 19 years of age (AAP, 1989; CDC, 1989a; CDC, 1990). MMR vaccination is generally considered safe and effective. Some common side effects include transient
Pediatric
Pharmacology
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rash, pruritus, and low-grade fever. Central nervous system conditions, such as encephalitis or encephalopathy, and febrile seizures have been reported within 30 days of MMR vaccination. Arthra!gia and transient arthritis have been reported after rubella vaccination, especially in adults (Markowitz & Orenstein, 1990). Because the vaccines are live, attenuated preparations, these products are contraindicated in pregnancy and immunocompromised or immunosuppressed individuals except persons infected with human immunodeficiency virus (HIV). For individuals who have a history of anaphylactic reactions to eggs or a hypersensitivity reaction to neomycin, the MMR vaccine is also contraindicated (CDC, 1989a; CDC, 1989b). However, some individuals with history of allergic manifestations after ingesting eggs have no reaction when skin tested with vaccine and tolerate vaccination without incident (AAP, 1991). For individuals who do not have anaphylactic symptoms, MMR vaccine may be administered (AAP, 1991). Vaccination should be postponed in persons with severe febrile illness until they have recovered. After receiving immune globulin, whole blood, or antibody-containing blood products, vaccines should not be administered sooner than 6 weeks and preferably not for 3 months because passively acquired antibodies may interfere with the response to the vaccine (AAP, 1989; AAP, 1991; CDC, 1989a; CDC, 1989b; CDC, 1990). If vaccines are to be administered before immune globulin, they should be administered approximately 2 weeks before immune globulin administration @Al?, 1989; AAP, 1991; CDC, 1989a; CDC, 1989b; CDC, 1990). MMR administration has not been associated with increased adverse reactions in HIV-infected patients, but antibody production may be unpredictable. Because some diseases, such as measles, may be more severe in HIV-infected individuals, both the ACIP and AAP recommend immunization for asymptomatic and symptomatic HIV-infected persons @AI’, 1989; AAP, 1991; CDC, 1989a; CDC, 1989b; CDC, 1990). REFERENCES Albrecht, P., Ennis, F. A., Saknan, E. J., & Krugman, S. (1977). Persistence of maternal antibody in infants beyond 12 months of age: mechanism of measles vaccine failure. Jownul of Pedhriq 91, 715718. American Academy of Pediatrics. (1989). Measles reassessment of the current immunization policy. Pediutria, 84, 1110-l 113. American Academy of Pediatrics. (1991). Report of the Committee of ZnfectMw Dlj,,,. Elk Grove Viiage, IL: American Academy of Pediatrics. American Academy of Pediatrics. (1992). Universal hepatitis B im munization: Committee of Infectious Disease. Pediatrirs, 89,795800. Barkin, R. M., & Pichichero, M. E. (1979). Diphtheria-pertwistetanus vaccine: reactogenicity of commercial products. Pedhia, 63, 256-260.
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Boyd, J. R. (Ed.). Fuets anri -ations (pp.460-464d, 468a-471b, & 852). St. Louis: JB Lippincott. Brady, M., & So&y, R. G. (1947). Neurologic complications following administration of pertussis vaccine. New York State Journal ofMcd.i&c, 47, 1016-1017. Byers, R. K., & Mall, F. C. (1948). Encephalopatbies following prophylactic pertussis vaccination. Pcdiacria, 1, 437-457. Centers for Disease Control. (1989a). Measles prevention: recommendations of the Immunization Practices Advisory Committee (ACIP). Morbidity andMorta& WccUy Report, 38, 1-18. Centers for Disease Control. (1989b). Mumps prevention: recommendations of the ACIP. Morb&y andMorta&y Weekly Report, 38, 388-392, 397-400. Centers for Disease Control. (1990). Rubella prevention: recommendations of the ACIP. Morbid&y andMortality We&y Rqwt, 39, 1-18. Centers for Disease Control. (1991a). Diphtheria, tetanus, and pertussis: recommendations for vaccine use and other preventive measures: recommendations of the ACIP. Morbia’@ and Mom&y WeekbyReport, 40, l-28. Centers for Disease Control. (1991b). Summary of notifiable diseases, United States, 1990. Morbid@ and Morta&v Wee&v Report, 39, 55-61. Centers for Disease Control. (1992). Pertussis vaccination: acellular pertussis vaccine for reinforcing and booster use - supplementary ACIP statement. Morhi$v andMortali~ Weekly Report, 41, l-10. Cody, C. L., BarafT, L. J., Cherry, J. D., Marcy, S. M., & Manclark, C. R. (1981). Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pcdiatria, 68, 650-660. Davis, R. M., Whitman, E. D., Orenstein, W. A., Preblud, S. R., Markowitz, L. E., & Hinman, k R. (1987). A persistent outbreak of measles despite appropriate control measures.A merican Jour& of E$&mio&y, 126, 438449. Dyer, C. (1988). Judge not satisfied that whooping cough vaccine causes permanent brain damage. Br&& Mcdieul Jmmul, 296, 1189-1190. Edwards, K. M., &Karzon, D. T. (1990). Pertussisvaccines. PEdiatric Cliti of North Amcricu, 37, 549-566. Frenkel, L. D. (1990). Routine immunizations for American children. Pediatric Clinia ofNorth Amwiq 37, 531-548. Greaves, W. L., Orenstein, W. A., Hinman, A. R., & Nersesian,
Volume 6, Number 6 November-December 1992
W. S. (1983). Clinical efficacy of rubella vaccine. Pediatvic Znfectious D&ace, 2, 284-286. Howson, C. P., & Fineberg, H. V. (1992). The ricochet of magic bullets: summary of the Institute of Medicine report, adverse effects of pertussis and rubella vaccines. Pcdiahq 89, 318-324. Kulenkampff, M., Schwarrzman, J. S., & Wilson, J. (1974). Neurological complications of pertussis inoculation. Arcbivcs ofDisease in Cbildbood, 49, 46-49. Livengood, J. R., Mullen, J. R., White, J. W., Brink, E. W., & Orenstein, W. A. (1989). Family history of convulsions and use of pertussis vaccine. Jorrmd ofPcdia& 11.5, 527-531. Long, S. S., Deforest, A., Pennridge Pediatric Associates, Smith, D. G., Lazaro, C., & Was&k, S. G. F. (1990). Longitudinal study of adverse reactions following diphtheria-tetanus-permssis vaccine in infancy. Pcdintrirs, 85, 294-302. Markowitz, L. E., & Orenstein, W. A. (1990). Measles vaccines. Pcdb&e Clinia of North Amcricu, 37, 603-625. Orenstein, W. A., Markowitz, L. E., Preblud, S. R., Hinman, A. R., Tomasi, A., & Bart, K. J. (1986). The appropriate age for measles vaccination in the United States. Denzen in BiologiEal Stanah&&n, 65, 13-21. Pichichero, M. E., Francis, A. B., Blatter, M. M., Reisinger, K. S., Green, J. L., Marsocci, S. M., & Disney, F. A. (1992). Acellular pertussis vaccination of 2-month-old infants in the United States. @diatria, 89, 882-887. Rutledge, S. L., & Snead, 0. C. III. (1986). Neurologic complications of immunizations. Journal of Pcdiatrirs, 109, 917-924. Shields, W. D., Nielsen, C., Buch, D., Jacobsen, V., Christenson, P., Zachau-Christenson, B., & Cherry, J. D. (1988). Relationship of pextussis immunization to the onset of neurologic disorders: a retrospective epidemiologic study. Journal of Pcdtizti, 113, Sol805. Sullivan, K. M., Halpin, T. J., Marks, J. S., & Kim-Farley, R. (1985). Effectiveness of mumps vaccine in a school outbreak. American Jounual of Dtieam of Children, 139, 909-912. Walker, A. M., Jick, H., Perera, D. R., Knauss, T. A., & Thompson, R. S. (1988). Neurologic events following diphtheria-tetanuspertussis immunization. Pcdiahq 81, 345-349. Wharton, M., Co&i, S. L., Hutcheson, R. H., Bistowish, J. M., & Schaffner, W. (1988). A large outbreak of mumps in the post vaccine era. Jmwnul of Infect& Dticase, 158, 1253- 1260.
Childhood Immunization . Part I . Cathy
Y. Poon,
T
he prevention of infectious diseases through worldwide immunization programs has reduced the incidence of serious contagious childhood illnesses. The benefits of immunization range from partial to complete protection against such diseases. However, immunization is not without risks. Risks range from mild to severe life-threatening side effects. Thus recommendations for immunization from the Committee on Infectious Diseasesof the American Academy of Pediatrics (AAP) and the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control (CDC) are made based on evidence of benefits, cost, and risks of adverse reactions to achieve optimal protection against certain infectious diseases. With the introduction of new products and the recognition of disease outbreaks, changes in vaccination recommendations occur frequently. Some recent changes include the administration of two doses instead of one dose of measles-mumps-rubella (MMR) vaccine, development of acellular pertussis vaccines, introduction of new Hemophilw b conjugate vaccines, and new recommendations for hepatitis B immunization. In a two-part series, the epidemiology, pathophysiology, and clinical manifestations of several preventable infectious diseases will be reviewed. Diphtheria, tetanus, pertussis, measles, mumps, rubella, and the vaccines used to prevent these illnesses will be discussed in Part I. . DIPHTHERIA, Diphtheria
TETANUS, AND PERTUSSIS
Diphtheria is caused by Cwynebacterium diphtheria. In 1921, more than 200,000 cases, primarily in children,
At the time of writing this paper, Dr. Cathy Y. Poon was a Clinical Instructor and a Postdoctoral Pediatric Pharmacotherapy Resident at the College of Pharmacy, the University of Oklahoma Health Sciences Center and Department of Pharmacy, Children’s Hospital of Oklahoma, Oklahoma City, Oklahoma.
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PharmD
were reported (CDC, 1991a), but today diphtheria is a rare disease in the United States because of vaccination programs. Approximately 97% of children in the United States are given at least three doses of diphtheria-tetanus-pertussis (DTP) vaccine before entering school (CDC, 1991a). Diphtheria is an acute infection of the skin or upper respiratory tract. Typically, C. diphtheria contaminates the skin at the site of a wound. The toxin elaborated by the microorganism then causes inflammation and destruction of the epithelium. A grey pseudomembrane is usually formed over the tonsils, larynx, and pharynx. The toxin often spreads to the heart, liver, kidneys, adrenal glands, and nervous system where damage may occur. Vaccination generally provides only 3 years of full immunity and 10 years of partial immunity (Frenkel, 1990). For the prevention of this disease, diphtheria toxoid is usually administered in combination with pertussis vaccine and tetanus toxoid (Table 1). Tetanus
Since the routine use of tetanus toxoid was instituted, tetanus cases in the United States declined from 560 in 1947 to 64 in 1990 (CDC, 1991b). The number of cases over the last decade has remained relatively constant, averaging about 70 cases per year (CDC, 1991b). Presently, tetanus is primarily a disease of older adults with two thirds of reported cases occurring in individuals 50 years of age or older (CDC, 1991a). Like diphtheria and pertussis, tetanus occurs exclusively among persons who are inadequately vaccinated or in infants whose umbilical stumps are contaminated with Costridium tetani. For infants born to mothers with appropriate immunization, protective immunity is conferred to the infant from the transplacental transfer of maternal antibodies. Fortunately, with improved prevention strategies, neonatal tetanus has declined. Two-thirds of tetanus cases follow minor puncture JOURNAL
OF PEDIATRIC
HEALTH
CARE
Journal
of
Pediatric
n
Health
TABLE
1
Pediatric
Care
Recommended
RECOM4iMW
schedule
for routine
AGE
Newborn 2 Months
4 Months
6 Months
HBV DTP OPV HbCV HBV DTP OPV HhCV DTP OPV HbCV HBV HbCV booster
MMR
HbCV booster
18 Months
DTP
OPV 4-6 Years (at or before entry to kindergarten or elementary school) 14-16 Years
DTP OPV MMR Td
371
of infants and children
VACCINES
12 Months
15 Months
immunization
Pharmacology
COMMEMTS
First dose of HBV is administered before hospital discharge. DTP may be given as eariy as 6 weeks of age, then at 4-S week intervals for the first three doses
-
HbCV may be given either as HbOC or PRP-OMP Second dose of HBV may be given between 1-2 months HbCV may be given either as HbOC or PRP-OMP
Optional dose of OPV, but recommended in high-risk areas If HbOC was used, recommend another dose at 6 months Third dose of HBV may be given between 6-18 months If PRP-OMP was used previously, recommend a HbCV booster dose given at 12 months as the third dose of PRP-OMP MMR is usually not given to infants younger than 15 months of age but may be given at 12 months in high-’ risk areas If HbOC was used previously, recommend another HbCV booster at 15 months, that may be given as PRP-OMP, PRP-D,or HbOC DTP may be given between 15-18 months, but usually between 6 and 12 months after the third dose, and may be given simultaneously with MMR at 15 months OPV may be given simultaneously with MMR and HbCV at 15 months or any time between 12 and 24 months DTP can be given up to seventh birthday
AAP recommends the administration of the second dose of MMR at 1 l-1 2 years of age Repeat every 10 years throughout life
Adapted from AAP, 1989; AAP, 1991; AAP, 1992; CDC, 1982; CDC, 1989a; CDC, 1989b; CDC, 1990; & CDC, 1991a. HBV, Hepatitis B virus vaccine (refer to Childhood immunization, Part II, for details); DTP, diphtheria toxoid, tetanus toxoid, whole-cell pertussis vaccine; OPV, oral poliovirus vaccine; HbCV, Hemophilus b conjugate vaccine (three preparations are available [refer to Childhood Immunization, Part II, for details]: PRP-D [ProHIBiTI, polyribosylribitoi phosphate conjugated to diphtheria toxoid; HbOC [HibTITERI, polyribosylribitoi phosphate oligosaccharide conjugated with a nontoxic mutant diphtheria toxin; PRP-OMP [PedvaxHIB], polyribosylribitol phosphate conjugated with an outer membrane protein of N. meningitidis); MMR, measles, mumps, rubella vaccine;Td, tetanus toxoid (full dose) and adult strength diphtheria toxoid.
wounds of the hands or feet. C. tetani produces a neu-
Pertussis
rotoxin, tetanospasmin, that causes severe muscle spasms. The onset of tetanus occurs gradually over 1 to 7 days after the puncture wound. UsuaIly, severe spasms of the jaw (lockjaw) are noted within 48 hours, followed by stiffhess of the neck, back, and abdominal muscles. Severe illness may result in swallowing difficulties and seizures. Severe spasms usually persist for 1 or more weeks and then gradually subside over several weeks. Tetanus toxoid contains antigens that induce protective concentrations of serum antitoxins that provide adequate protection against tetanus for approximately 10 years. Secondary immunization or boosters are required every 10 years after the primary immunization series to maintain appropriate antitoxin levels for individuals of all ages (Table 1). DTP is preferred by the AAP and ACIP for childhood tetanus immunization.
Pertussis or whooping cough was once a major cause of infant and childhood morbidity and death in the United States. In 1934 at the peak incidence of pertussis disease, 265,269 cases were reported, with 1,718 deaths (CDC, 1991a). With the introduction of pertussis vaccine, reported cases declined to 1,730 cases in 1980 (CDC, 1991a). Because of negative publicity surrounding adverse reactions associated with pertussis vaccine (Kulenkampff, Schwartzman, &Wilson, 1974)) vaccine use declined dramatically over the last decade. This has lead to a steady increase in the incidence of pertussis from 1,248 cases in 1980 to 4,570 in 1990, with an average of eight deaths per year (CDC, 1991b). Pertussis is caused by a small fastidious gram-negative bacillus Bordetella pertush. Pertussis is a highly contagious respiratory tract infection that causes a 90% in-
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Pharmacology
fection rate in household contacts of index cases (Frenkel, 1990). Pertussis is most severe in young children and may cause pneumonia, seizures, and encephalopathy. Infection may present with severe bronchitis, rhinitis, sneezing, and coughing. The cough may become paroxysmal with 10 to 30 coughs ending in a loud inspiratory “whoop,” hence the term whooping wu~~. The first pertussis vaccine was developed in 1925. In the late 194Os, standardized whole-cell pertussis vaccines combined with diphtheria and tetanus toxoid were developed and are still used today (Table 2). Because of adverse reactions reported for pertussis vaccine (Cody, Baraff, Cherry, Marcy, & Manclark, 198 1; Long et al., 1990), recent efforts have focused on developing safer, effective pertussis vaccines. Acellular pertussis vaccines have been developed that provide protective immunity with potentially fewer adverse reactions. Recently, a diphtheria, tetanus toxoid, and acellular pertussis vaccine (DTaP) was licensed as Acel-Imune (Lederle Laboratories, Pearl River, N. Y .) in the United States. This vaccine is recommended only for the fourth and fifth doses of DTP vaccination, and it is not licensed for the first three dose series regardless of age (CDC, 1992). Pichichero et al. (1992) recently evaluated the immunogenicity of and adverse reactions to another DTaP preparation in young children who were given the product for primary immunization. This acellular vaccine was compared to whole-cell pertussis vaccine in 388 infants. The investigators concluded that this DTaP vaccine when given as a primary series produced greater immunogenicity and fewer adverse reactions than whole-cell DTP (Pichichero et al., 1992). However, based on experiences in Sweden and Japan with acellular pertussis vaccines, effective protective immunity is questionable when the vaccine is administered during early infancy. Therefore whole-cell pertussis vaccine is recommended for primary immunization in infants until further studies show equivalent or superior efficacy and safety with DTaP. The incidence of adverse reactions to whole-cell pertussis vaccines has been assessed in several large studies (Barkin & Pichichero, 1979; Cody et al., 1981; Rutledge & Snead, 1986; Shields et al., 1988; Walker, Jick, Perera, Knauss & Thompson, 1988). The vaccine has been associated with relatively mild, local and severe, systemic reactions. Some local reactions include redness, tenderness, and swelling. Fever, crying, and irritability are often noted. These are common, nonspecific side effects that are generally seen within 12 to 24 hours after vaccination. Serious, uncommon reactions include persistent, high-pitched crying; convulsions, frequently associated with fever; and hypotonic responses. The most severe reaction reported with whole-cell pertussis vaccine administration is encephalopathy resulting in
permanent brain damage or death (Brody & Sorley, 1947; Byers & Moll, 1948). To date, whole-cell pertussis vaccine has not been statistically linked to encephalopathy, neurologic damage, or death (Edwards & Karzon, 1990). A recent report by the Institute of Medicine (Howson & Fineberg, 1992) addresses the controversies surrounding the safety of whole-cell pertussis vaccine. The Institute concluded that the evidence reviewed is consistent with a causal relation between DTP vaccine and acute encephalopathy. Presently, the general consensus held by many clinicians is that the pertussis vaccine helps unmask underlying central nervous system manifestations, but the vaccine does not directly engender an encephalopathic state (Dyer, 1988; Shields et al., 1988; Walker et al., 1988). DTP Vaccine
Diphtheria and tetanus toxoids and pertussis vaccine are available as single antigen or in various combinations (Table 2). DTP is the preparation recommended by the AAP and ACIP, unless otherwise contraindicated. The diphtheria and tetanus toxoid (Td) preparation is recommended for individuals older than 7 years of age. It contains one-eighth to one-tenth of the diphtheria dose found in DTP or DT (diphtheria and tetanus toxoid preparation for pediatric use) because side effects are more likely and generally are more severe in older children and adults. Additionally, boosting of immunity in older children and adults may be elicited with smaller toxoid doses (Frenkel, 1990). If a combination product is contraindicated, single-antigen products are recommended. The administration of a preparation that contains pertussis vaccine should be done cautiously because it is usually the pertussis component that is responsible for most serious adverse reactions. Absolute contraindications for further DTP vaccination include the experiencing of an immediate anaphylactic reaction or encephalopathy that occurs within 7 days after DTP vaccination. The occurrence of any of the following adverse effects within 48 hours after vaccination should be a precaution or warning that further vaccinating should be done only when benefits outweigh risks: a temperature of 40.5” C (105“ F) or more of unknown cause; collapse or shock-like state (hypotonic-hyporesponsive episode); and persistent, inconsolable crying lasting 3 hours or more. Also listed as a precaution to vaccination is the development of convulsions, with or without fever, within 3 days after vaccination (CDC, 1991a). Infants and young children who have a history of seizures are at an increased risk of seizures after DTP (Livengood, Mullen, White, Brink, & Orenstein, 1989). The only contraindication to the administration of diphtheria toxoid or tetanus toxoid is a history of a
Journal of Pediatric Health
Pediatric
Care
TABLE 2 Vaccines and toxoids and rubella
n
GENERIC
available
Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) Diphtheria and tetanus toxoids, adsorbed (TD) (for pediatric use only)
Diphtheria and tetanus toxoids, adsorbed (Td) (for adult use only)
Tetanus toxoid,
adsorbed
Tetanus toxoid,
fluid
Measles, mumps, and rubella virus vaccine, live (MMR) Measles (rubeola) virus vaccine, live, attenuated (M) Mumps virus vaccine, live Rubella virus vaccine,
live (R)
Measles (rubeola) and rubella virus vaccine, live (MR) Rubella and mumps virus vaccine, live Adapted from companies.
States as diphtheria,
MANUFACTURER (TRADE NAME)
NAME
Diphtheria and tetanus toxoids and pertussis vaccine, adsorbed (D-W
in the United
Pharmacology
373
tetanus, pertussis, measles, mumps, STORAGE REQUIREMENTS
DOSE
Connaught Laboratories, Inc. Lederle Laboratories (TriImmunol) Lederle Laboratories (Acel-lmune) Connaught Laboratories, Inc. Lederle Laboratories Sclavo, Inc. Wyeth-Ayerst Laboratories Connaught Laboratories, Inc. Lederle Laboratories Sclavo, Inc. Wyeth-Ayerst Laboratories Connaught Laboratories, Inc. Lederle Laboratories Sclavo, Inc. Wyeth-Ayerst Laboratories Connaught Laboratories, Inc. Wyeth-Ayerst Laboratories Merck, Sharp & Dohme (M-M-R II) Merck, Sharp & Dohme (Attenuvax) Merck, Sharp & Dohme (Mumpsvax) Merck, Sharp & Dohme (Meruvax II) Merck, Sharp & Dohme (M-R-Vax II) Merck, Sharp & Dohme (Biavax)
Boyd, J.R. (Ed.). Facts and comparisons
(pp. 460-463,
468a-471
neurologic or severe hypersensitivity reaction after a previous dose of either toxoid. Although pregnancy is not a contraindication for diphtheria or tetanus immunization, the recommendation is to delay administration of Td until the second trimester to minimize any potential for teratogenic reactions (CDC, 1991a). DTP is recommended by the ACIP and AAP for primary immunization against diphtheria, tetanus, and pertussis. For children 6 weeks through 6 years of age, primary immunization includes four doses of the DTP vaccine (Table 1). If pertussis vaccine is contraindicated,
0.5 ml intramuscularly
Store at 2” to 8” C; do not freeze.
1
0.5 ml intramuscularly cutaneously
or sub-
Before and after reconstitution, store at 2” to 8” C; protect from light; reconstitute before use; discard if not used within 8 hours.
0.5 ml subcutaneously
b, & 852).
St. Louis: 1.8. Lippincott.
Verified
by author
communication
with all
DT should be administered instead of DTP. For children who have not received any DTP immunizations by 1 year of age, an alternate schedule is recommended (American Academy of Pediatrics, 1991; CDC, 1991a). A DTP booster should be administered before school enrollment, between 4 and 6 years of age. Subsequent booster injections, given as Td, are recommended at lo-year intervals throughout life beginning at age 14 to 16 years, or 10 years after the last DTP dose (Table 1). A child born under unhygienic conditions to a
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Volume 6, Number 6 November-December 1992
Pharmacology
woman who has not been vaccinated against tetanus is at risk for neonatal tetanus. To provide some protection for such an infant, the mother should be given two doses of Td 4 to 8 weeks apart during the last trimester before delivery (CDC, 199 la). n MEASLES, MUMPS, AND RUBELLA Measles (Rubeola)
Measles was once the most common vaccine-preventable cause of death among children worldwide, with an estimated 2.5 million deaths occurring annually during the early 1980s (Markowitz & Orenstein, 1990). Secondary to worldwide immunization efforts, measles has become a rare disease in many countries. However, outbreaks continue to occur, particularly in two susceptible groups: unvaccinated preschool-aged children and in previously vaccinated individuals secondary to vaccine failure. In the United States, reported measles cases increased almost sixfold from 1988 to 1989. The number of cases then increased another 50% in the next year to 27,786 cases (CDC, 1991b). Failure to eliminate or prevent measles has lead to new recommendations for measles vaccination. A second dose of measles vaccine was recommended by the ACIP and AAP in 1989. Measles is an acute, highly contagious systemic infection, which most commonly affects preschool-aged children. The primary infection site is the respiratory epithelium of the nasopharynx. Measles is considered communicable from 1 to 2 days before and for 4 days after the onset of rash. During this period, measles may be transmitted by direct contact. After an incubation period, a prodrome consisting of fever and malaise typically develops. Then cough, coryza, and conjunctivitis follow. Koplik? spots, a pathognomonic enanthema, are characterized by small bluish-white spots on the buccal mucosa that can be noted during the prodrome period. A characteristic rash usually appears 2 to 4 days after the onset of prodromal symptoms. The rash generally starts on the face, then spreads to the trunk and extremities. Initially, it is a maculopapular rash, but over the next week the rash gradually becomes confluent and slowly fades. Several measles vaccines were developed in the 1960s. The Enders’ attenuated Edmonston strain measles vaccine, which is found in the trivalent MMR vaccine commonly used today (Table 2), induced both humoral and cellular immune responses. The efficacy for this vaccine used in the United States is more than 95% when administered to children after 12 months of age (Davis et al., 1987). Primary vaccination failure is directly related to seroconversion rates after vaccine administration and appears to be age dependent. Epidemiologic studies have shown a higher attack rate for measles among persons vaccinated before 12 months of age compared to those vaccinated at 15 months of age
or older (Orenstein et al., 1986). This may occur because maternal antibodies may persist beyond 12 months of age; an adequate immune response may not be mounted when an infant is vaccinated too early (Albrecht, Ennis, Saltzman, & Krugman, 1977). Lifelong immunity is usually conferred with one disease exposure; however, measles vaccination does not guarantee lifelong immunity. Mumps
Mumps is a communicable disease of children and young adults that may affect most organs in the body, but 30% to 40% of those who contract mumps are asymptomatic. Mumps is most common in children between the ages of 5 and 9 years, but the disease is generally more severe in older children and adults. One episode of the disease, clinical or subclinical, generally provides lifelong immunity. After the introduction of mumps vaccine in the United States, reported cases of mumps have declined dramatically to a low of 2,982 cases in 1985. In 1987, a fivefold increase in reported cases occurred, but since then, the number of cases has decreased to approximately 5,000 between 1988 and 1990 (CDC, 1991b). Infection occurs through direct respiratory contact. Once infected, the virus replicates in the nasopharyngeal mucosa and lymph node regions and presumably causes a primary viremia. This may lead to viral seeding of various organs. Parotid involvement is the most common and distinctive manifestation of mumps. Central nervous system involvement may present as headache, mental confusion, stiff neck, and cerebral spinal fluid abnormalities. Mumps infection during the first trimester of pregnancy can increase the risk of spontaneous abortion; however, once the virus crossesthe placenta, no evidence exists that it causes congenital malformations. Live, attenuated mumps vaccine was licensed in 1967 and was recommended for routine use in 1977. Efficacy rates are between 75% and 91% (Sullivan, Halpin, Marks, & Kim-Farley, 1985; Wharton, Cochi, Hutcheson, Bistowish, & Schaffher, 1988). Evidence supports that protective immunity persists for 20 years after vaccination. Mumps vaccination is effective when administered any time after the disappearance of passively acquired maternal antibody, usually about 1 year of age. Mumps vaccine is usually given as part of the trivalent preparation, MMR (Table 1). Rubella (German Measles)
In the prevaccination era, rubella was a common childhood disease. Most cases occurred in children between the ages of 5 and 9 years. Since the introduction of rubella vaccine in 1969, rubella caseshave declined from 57,686 to 1,125 in 1990. Rubella is acquired through droplet contact from nasopharyngeal secretions. Viral
Journal of Pediatric Health Care
replication takes place in the nasopharyngeal mucosa and causes a transient viremia. Postnatal rubella is generally mild and self-limiting. The most common manifestations include transient erythematous rash (sometimes pruritis), low-grade fever, arthralgia, and lymphadenopathy. The most significant consequences of rubella are miscarriages, stillbirths, fetal anomalies, and abortions that result from rubella infection during pregnancy, especially in the first trimester. Because of the serious fetal effects, immunization programs have been targeted at women of childbearing age before pregnancy to prevent or eliminate congenital rubella syndrome (CRS) . CRS is a severe, disseminated, and chronic form of rubella that may affect every organ system. The most common anomalies associated with CRS are auditory, ophthalmic, cardiac, and neurologic. Rubella vaccine is available in combination with measles and/or mumps or as monovalent preparation (Table 2). The live rubella-virus vaccine currently distributed in the United States is prepared in human diploid cell cultures, RA 27/3. The present vaccine is more immunogenic, provides a greater resistance to reinfection, and has lower reaction rates than older products. After proper vaccination, protection against clinical rubella and viremia for at least 15 years develops in about 90% of those being vaccinated (Greaves, Orenstein, Hinman, & Nersesian, 1983). MMR
Vaccine
The most commonly administered vaccine for measles, mumps, and rubella is the trivalent preparation, MMR. Combinations and single-antigen preparations that contain live, attenuated antigens are available for MMR (Table 2). The AAP and ACIP recommend the administration of MMR vaccine for immunization in all susceptible individuals, unless one or more of the components are contraindicated. Two doses are recommended, with the first dose administered at 15 months of age, except for children in high-risk areas who should receive the first dose at 12 months of age. Both Cornmittees agree that a second MMR immunization should be administered to insure immunity and avoid vaccine failure. The ACE’ recommends that the second dose be administered between 4 and 6 years of age or before grade school entry. By receiving this MMR dose at the same time as DTP, the need to make an additional visit to a health care provider is eliminated, the risk of noncompliance or poor follow-up decreases. The AAI’ recommends that the second MMR dose be administered at age 11 to 12 years because documentation has shown that most measles and/or rubella vaccination failures occur between 10 and 19 years of age (AAP, 1989; CDC, 1989a; CDC, 1990). MMR vaccination is generally considered safe and effective. Some common side effects include transient
Pediatric
Pharmacology
375
rash, pruritus, and low-grade fever. Central nervous system conditions, such as encephalitis or encephalopathy, and febrile seizures have been reported within 30 days of MMR vaccination. Arthra!gia and transient arthritis have been reported after rubella vaccination, especially in adults (Markowitz & Orenstein, 1990). Because the vaccines are live, attenuated preparations, these products are contraindicated in pregnancy and immunocompromised or immunosuppressed individuals except persons infected with human immunodeficiency virus (HIV). For individuals who have a history of anaphylactic reactions to eggs or a hypersensitivity reaction to neomycin, the MMR vaccine is also contraindicated (CDC, 1989a; CDC, 1989b). However, some individuals with history of allergic manifestations after ingesting eggs have no reaction when skin tested with vaccine and tolerate vaccination without incident (AAP, 1991). For individuals who do not have anaphylactic symptoms, MMR vaccine may be administered (AAP, 1991). Vaccination should be postponed in persons with severe febrile illness until they have recovered. After receiving immune globulin, whole blood, or antibody-containing blood products, vaccines should not be administered sooner than 6 weeks and preferably not for 3 months because passively acquired antibodies may interfere with the response to the vaccine (AAP, 1989; AAP, 1991; CDC, 1989a; CDC, 1989b; CDC, 1990). If vaccines are to be administered before immune globulin, they should be administered approximately 2 weeks before immune globulin administration @Al?, 1989; AAP, 1991; CDC, 1989a; CDC, 1989b; CDC, 1990). MMR administration has not been associated with increased adverse reactions in HIV-infected patients, but antibody production may be unpredictable. Because some diseases, such as measles, may be more severe in HIV-infected individuals, both the ACIP and AAP recommend immunization for asymptomatic and symptomatic HIV-infected persons @AI’, 1989; AAP, 1991; CDC, 1989a; CDC, 1989b; CDC, 1990). REFERENCES Albrecht, P., Ennis, F. A., Saknan, E. J., & Krugman, S. (1977). Persistence of maternal antibody in infants beyond 12 months of age: mechanism of measles vaccine failure. Jownul of Pedhriq 91, 715718. American Academy of Pediatrics. (1989). Measles reassessment of the current immunization policy. Pediutria, 84, 1110-l 113. American Academy of Pediatrics. (1991). Report of the Committee of ZnfectMw Dlj,,,. Elk Grove Viiage, IL: American Academy of Pediatrics. American Academy of Pediatrics. (1992). Universal hepatitis B im munization: Committee of Infectious Disease. Pediatrirs, 89,795800. Barkin, R. M., & Pichichero, M. E. (1979). Diphtheria-pertwistetanus vaccine: reactogenicity of commercial products. Pedhia, 63, 256-260.
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Boyd, J. R. (Ed.). Fuets anri -ations (pp.460-464d, 468a-471b, & 852). St. Louis: JB Lippincott. Brady, M., & So&y, R. G. (1947). Neurologic complications following administration of pertussis vaccine. New York State Journal ofMcd.i&c, 47, 1016-1017. Byers, R. K., & Mall, F. C. (1948). Encephalopatbies following prophylactic pertussis vaccination. Pcdiacria, 1, 437-457. Centers for Disease Control. (1989a). Measles prevention: recommendations of the Immunization Practices Advisory Committee (ACIP). Morbidity andMorta& WccUy Report, 38, 1-18. Centers for Disease Control. (1989b). Mumps prevention: recommendations of the ACIP. Morb&y andMorta&y Weekly Report, 38, 388-392, 397-400. Centers for Disease Control. (1990). Rubella prevention: recommendations of the ACIP. Morbid&y andMortality We&y Rqwt, 39, 1-18. Centers for Disease Control. (1991a). Diphtheria, tetanus, and pertussis: recommendations for vaccine use and other preventive measures: recommendations of the ACIP. Morbia’@ and Mom&y WeekbyReport, 40, l-28. Centers for Disease Control. (1991b). Summary of notifiable diseases, United States, 1990. Morbid@ and Morta&v Wee&v Report, 39, 55-61. Centers for Disease Control. (1992). Pertussis vaccination: acellular pertussis vaccine for reinforcing and booster use - supplementary ACIP statement. Morhi$v andMortali~ Weekly Report, 41, l-10. Cody, C. L., BarafT, L. J., Cherry, J. D., Marcy, S. M., & Manclark, C. R. (1981). Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pcdiatria, 68, 650-660. Davis, R. M., Whitman, E. D., Orenstein, W. A., Preblud, S. R., Markowitz, L. E., & Hinman, k R. (1987). A persistent outbreak of measles despite appropriate control measures.A merican Jour& of E$&mio&y, 126, 438449. Dyer, C. (1988). Judge not satisfied that whooping cough vaccine causes permanent brain damage. Br&& Mcdieul Jmmul, 296, 1189-1190. Edwards, K. M., &Karzon, D. T. (1990). Pertussisvaccines. PEdiatric Cliti of North Amcricu, 37, 549-566. Frenkel, L. D. (1990). Routine immunizations for American children. Pediatric Clinia ofNorth Amwiq 37, 531-548. Greaves, W. L., Orenstein, W. A., Hinman, A. R., & Nersesian,
Volume 6, Number 6 November-December 1992
W. S. (1983). Clinical efficacy of rubella vaccine. Pediatvic Znfectious D&ace, 2, 284-286. Howson, C. P., & Fineberg, H. V. (1992). The ricochet of magic bullets: summary of the Institute of Medicine report, adverse effects of pertussis and rubella vaccines. Pcdiahq 89, 318-324. Kulenkampff, M., Schwarrzman, J. S., & Wilson, J. (1974). Neurological complications of pertussis inoculation. Arcbivcs ofDisease in Cbildbood, 49, 46-49. Livengood, J. R., Mullen, J. R., White, J. W., Brink, E. W., & Orenstein, W. A. (1989). Family history of convulsions and use of pertussis vaccine. Jorrmd ofPcdia& 11.5, 527-531. Long, S. S., Deforest, A., Pennridge Pediatric Associates, Smith, D. G., Lazaro, C., & Was&k, S. G. F. (1990). Longitudinal study of adverse reactions following diphtheria-tetanus-permssis vaccine in infancy. Pcdintrirs, 85, 294-302. Markowitz, L. E., & Orenstein, W. A. (1990). Measles vaccines. Pcdb&e Clinia of North Amcricu, 37, 603-625. Orenstein, W. A., Markowitz, L. E., Preblud, S. R., Hinman, A. R., Tomasi, A., & Bart, K. J. (1986). The appropriate age for measles vaccination in the United States. Denzen in BiologiEal Stanah&&n, 65, 13-21. Pichichero, M. E., Francis, A. B., Blatter, M. M., Reisinger, K. S., Green, J. L., Marsocci, S. M., & Disney, F. A. (1992). Acellular pertussis vaccination of 2-month-old infants in the United States. @diatria, 89, 882-887. Rutledge, S. L., & Snead, 0. C. III. (1986). Neurologic complications of immunizations. Journal of Pcdiatrirs, 109, 917-924. Shields, W. D., Nielsen, C., Buch, D., Jacobsen, V., Christenson, P., Zachau-Christenson, B., & Cherry, J. D. (1988). Relationship of pextussis immunization to the onset of neurologic disorders: a retrospective epidemiologic study. Journal of Pcdtizti, 113, Sol805. Sullivan, K. M., Halpin, T. J., Marks, J. S., & Kim-Farley, R. (1985). Effectiveness of mumps vaccine in a school outbreak. American Jounual of Dtieam of Children, 139, 909-912. Walker, A. M., Jick, H., Perera, D. R., Knauss, T. A., & Thompson, R. S. (1988). Neurologic events following diphtheria-tetanuspertussis immunization. Pcdiahq 81, 345-349. Wharton, M., Co&i, S. L., Hutcheson, R. H., Bistowish, J. M., & Schaffner, W. (1988). A large outbreak of mumps in the post vaccine era. Jmwnul of Infect& Dticase, 158, 1253- 1260.
