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Routine vaccines across the life span, 2003. (Clinical Review).

This review of the recommendations for routine vaccines includes those used on the Recommended Childhood Immunization Schedule and the Recommended Adult Immunization Schedule. The rationale is provided for recent changes, such as encouraging influenza vaccination of healthy children aged 6 through 23 months and recommending that annual influenza vaccination begin at age 50. The risks and benefits of vaccination are discussed, including disease burden, rationale for vaccination, efficacy, adverse reactions, and recommendations. Pictures of vaccine-preventable diseases are included.

* KEY WORDS Hepatitis B vaccine; pertussis vaccine; poliovirus vaccine; measles vaccine; varicella vaccine; bacterial vaccines; influenza vaccine

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KEY POINTS FOR CLINICIANS

* Annual influenza vaccination is encouraged for healthy children 6 to 23 months of age.

* Pneumococcal conjugate vaccine is recommended at ages 2, 4, 6, and 12 to 15 months.

* Varicella vaccine is efficacious and recommended at ages 12 to 18 months.

The impact of routine vaccination on childhood diseases in the United States (Table 1) is so great that immunizations are considered one of the major medical achievements of the 20th century.

We discuss categories of indications for vaccination, based on age (see the Recommended Childhood Immunization Schedule and Recommended Adult Immunization Schedule in the color section) and other factors, including disease burden, rationale for vaccination, vaccine efficacy, adverse reactions, and recommendations.

HEPATITIS B VACCINE

Disease burden

Incidence and prevalence. Between 128,000 and 320,000 persons are infected annually in the United States with hepatitis B virus (HBV); clearly HBV infection represents a major health problem. The number of persons chronically infected with HBV--each of whom is potentially infectious--is estimated at 1.25 million; the lifetime risk for acquiring HBV infection has been estimated at 5%. (1)

Morbidity: chronic vs. acute infection. HBV infection is much more likely to become chronic when it is acquired early in life than in adulthood. Chronic HBV infection develops in

* 90% of those infected as infants

* 30% to 60% of those infected before age 4

* 5% to 10% of those infected as adults (1)

Therefore, although most acute HBV infections in the United States occur in adulthood because of high-risk behaviors, 36% of all persons in the United States with chronic HBV infection contracted the infection during childhood. (2)

Mortality. Up to 25% of individuals infected with HBV as infants will die of HBV-related chronic liver disease as adults. (2) Approximately 6,000 persons die annually of HBV-related liver disease (Table 1). In fact, HBV infection is the second leading cause of cancer worldwide. Most of these deaths occur in persons with chronic HBV infection and are caused by cirrhosis or primary hepatocellular carcinoma (color Figure 1).

[FIGURE 1 OMITTED]

Route of transmission. HBV can be contracted from persons either acutely or chronically infected. Transmission occurs primarily by blood exchange (e.g., via shared needles during injection drug use) or by sexual contact. The source of infection in 30% to 40% of hepatitis B cases cannot be determined. (3) These cases may result from underreporting of injection chug use and sexual activity and inapparent contamination of skin lesions or mucosal surfaces. Hepatitis B surface antigen (HBsAg) has been found in impetigo lesions and saliva of persons chronically infected with HBV, and on toothbrush racks and coffee cups in their homes. (4) Epidemiologic studies have shown that HBV can be transmitted between preschool-aged children. (5-8)

Rationale for routine hepatitis B vaccination

Routine infant vaccination against HBV is recommended for the following reasons:

* HBV infection results in high morbidity and mortality, especially if the infection is contracted in childhood.

* Although it is relatively infrequent, transmission of HBV infection from child to child has been reported in schools, daycare centers, families, and among playmates. (5,6,8,9)

* No risk factor for HBV infection can be identified in at least 30% of infected persons. (3,10,11) Strategies focusing on immunization of high-risk persons have had little impact.

* Those who engage in high-risk behaviors (e.g., injection drug use) often are not compliant with the three-dose vaccination regimen. Many become infected soon after beginning such behaviors.

* Routine infant hepatitis B vaccination is as cost-effective as other commonly used preventive measures. (12,13) Based on direct medical expenses, the estimated cost per year of life saved is $1,522 for routine infant vaccination. From a societal perspective, routine infant vaccination is cost-saving. (13)

Hepatitis B vaccines

The hepatitis B vaccines currently produced in the United States are manufactured by recombinant DNA technology using baker's yeast. They do not contain human plasma. Preexposure vaccination results in protective antibody levels in almost all infants and children (>95%).

Duration of immunity. Although antibody levels may slowly diminish with time following vaccination, most persons remain protected by the immunologic memory in B lymphocytes. Combined with the long incubation period of hepatitis B infection, this allows most immunized persons whose titers diminish to mount an anamnestic immune response if challenged by HBV.

A few persons who responded adequately to hepatitis B vaccine have developed HBV infection when exposed years after vaccination. None of those so infected in the United States have become chronically infected or developed serious complications such as chronic liver disease.

The issue of waning antibody levels in some healthy persons needs further study, but current data indicate excellent long term efficacy in preventing serious HBV infection in both infants and adults.

Although some expenses speculate that booster doses might be needed, they are not currently recommended. Of note, the duration of immunity in hemodialysis patients, in contrast to healthy per sons, appears to persist only as long as the level of antibody to hepatitis B surface antigen (anti-HBs) is [greater than or equal to] 10 mlU/mL.

Factors affecting immunogenicity. The number of doses administered affects immunogenicity. After the third close of hepatitis B vaccine, more than 95% of children seroconvert (i.e., develop [greater than or equal to] 10 mIU/mL of anti-HBs). The third dose is required for optimal protection; geometric mean titers improve with longer intervals between the second and third doses. Over 90% of healthy adults younger than 40 years of age seroconvert after being vaccinated. However, immunogenicity declines with age, dropping to 75% for recipients 60 years of age.

Underlying medical conditions associated with lower likelihood of seroconversion include prematurity with low birth weight, immunosuppression, renal failure, obesity, and tobacco use. In comparison to full-term infants, premature infants with a birth weight less than 2 kg have lower seroconversion rates; rates drop further if the birth weight is less than 1 kg. Therefore, hepatitis B vaccination should be delayed in preterm infants weighing less than 2 kg unless the infant is born to a HBsAg-positive mother (see "Vaccine Schedules and Procedures, 2003").

Vaccine efficacy. Efficacy (i.e., protection against HBV infection) is 80% to 95% for hepatitis B vaccines licensed in the United States when given to susceptible infants, children, and adults.

Adverse reactions. The most common adverse event after administration of hepatitis B vaccine is pain at the injection site, which occurs in 13% to 29% of adults and 3% to 9% of children. (1) Mild, transient systemic adverse events such as fatigue and headache have been reported in 11% to 17% of adults and 8% to 18% of children. Temperature greater than 37.7[degrees]C has been reported in 1% to 6% of vaccinees. Childhood hepatitis B vaccines in the United States are now free of thimerosal. A large study in the United States found no association between hepatitis B vaccine and multiple sclerosis. (14)

Recommendations

The prevalence of HBV infection and its associated morbidity and mortality have led to the development of a comprehensive hepatitis B vaccination policy that includes recommendations for

* Prevention of perinatal HBV infection

* Routine infant vaccination

* Catch-up vaccination of adolescents not previously vaccinated

* Catch up vaccination of young children at high risk for infection

* Preexposure vaccination of adults based on lifestyle or environmental, medical, and occupational situations that place them at risk.

The Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP) recommend hepatitis B vaccination for all infants, and catch-up vaccination for unvaccinated children and adolescents of any age. (15) The schedule for hepatitis B vaccine for infants depends on the mother's HBsAg status and birth weight; the dosage varies by age and indication (see Table 1 and text in "Vaccine Schedules and Procedures, 2003").

Post-vaccination testing. Post-vaccination testing for anti-HBs is recommended only when the results will affect the individual's subsequent medical care. Such persons include dialysis patients, infants born to HBsAg-positive mothers, sexual contacts of persons chronically infected with HBV, and health care workers at high risk of percutaneous or permucosal exposure to body fluids. Testing should be performed 1 to 2 months after completion of the vaccine series, with the exception of infants born to HBsAg-positive mothers, who should be tested at 9 to 15 months of age. An adequate antibody response to vaccination is 10 mlU/mL. Post vaccination testing is not indicated after routine vaccination of infants, children, adolescents, or persons at low risk of exposure (e.g., public safety workers and health-care workers who do not have contact with patients or their body fluids).

Revaccination. Revaccination is recommended for persons whose post-vaccination level of anti-HBs is less than 10 mlU/mL. Such persons should receive three doses on a 0-, 1-, and 6-month schedule. Antibody testing should be conducted again 1 to 2 months after revaccination. Persons who do not respond after two series (six doses) of hepatitis B vaccine should he counseled about universal precautions and the need lot hepatitis B immune globulin (HBIG) if they are exposed. Also, testing such persons for HBsAg should be considered, because some may already be chronically infected. Hemodialysis and immunocompromised patients at risk for infection should have serological tests annually and should be given a booster dose when antibody levels decline to less than 10 mlU/mL.
SPECIAL TOPIC

Prevention of perinatal HBV
infection

According to the ACIP, the American College
of Obstetricians and Gynecologists, the AAP,
and the U.S. Preventive Services Task Force,
all pregnant women should be screened for
HBsAg, optimally at an early prenatal visit. (16)
According to published calculations, screening
all pregnant women in the United States
would result in detection of about 22,000
HBsAg-positive women each' year and prevent
chronic HBV infection in 6,000 neonates
annually. (17) Women whose initial HBsAg test
result is negative but who are at high risk for
HBV infection (e.g., women who use injection
drugs, have a recently diagnosed sexually
transmitted disease, have multiple sexual
partners, or had hepatitis during pregnancy)
should be tested again for HBsAg late in
pregnancy. Infants born to HBsAg-positive
mothers should receive at separate sites hepatitis
B vaccine and 0.5 mL of HBIG within
12 hours of birth.


PERTUSSIS VACCINE

Disease burden

Most hospitalizations and serious complications of" pertussis occur in infants. About half of reported cases occur in infants, and three out of four occur in children younger than 5 years of age. (18)

Morbidity and mortality. Of reported cases of pertussis in infants younger than 12 months of age, 69% require hospitalization. (18) The case fatality rate is 0.6% for infants younger than 12 months of age. Females are somewhat more likely to exhibit clinical pertussis than males, probably due to smaller airway size.

Complications. Complications of pertussis include pneumonia, seizures, encephalopathy, and permanent brain damage. Pneumonia occurs in about 15% of pertussis cases (18) and is the leading cause of death from pertussis. Seizures occur in 2.2% of cases of pertussis and encephalopathy occurs in 0.7% of cases. (18) Encephalopathy, which may be caused by hypoxia or minute cerebral hemorrhages, is fatal in approximately one-third of cases and causes permanent brain damage in another one-third.

Route of transmission. Pertussis is transmitted by respiratory droplets and occasionally by contact with freshly contaminated objects. Adults and adolescents are the primary source of pertussis infection for young infants.

Pertussis is highly contagious: from 70% to 100% of susceptible household contacts (19) and 50% to 80% of susceptible school contacts will become infected following exposure to a person who is contagious. A person is contagious from 7 days after exposure to 3 weeks after symptom onset.

The incubation period ranges from 5 to 21 days and is typically 7 to 10 days.

Immunity following pertussis disease lasts for many years and is possibly lifelong. Transplacental immunity wanes rapidly following birth.

Rationale for routine pertussis vaccination

Before routine pertussis vaccination of children, peaks in whooping cough incidence occurred approximately every 3 to 4 years; virtually all children were infected. Between 1925 and 1930, 36,013 persons died in the United States due to complications from pertussis. From 1940 through 1945, more than 1 million cases of pertussis were reported in the United States. (19) By the mid-1940s, pertussis vaccination had become widespread. Incidence dropped by more than 95%, although the number of pertussis cases has increased in recent years, reaching 7,867 cases in 2000.

Vaccines. Although the whole-cell (DTP) pertussis vaccine has been quite effective in reducing pertussis disease, it has some adverse effects. Consequently, international efforts focused on developing an acellular vaccine with fewer adverse effects, using antigens from Bordetella pertussis. These antigens were thought to affect the organism's ability to cause disease; therefore, they might be important in an acellular vaccine. These include: 1) tracheal cytotoxin that destroys cilia, making it difficult to clear thickened mucus; 2) pertussis toxin (also called lymphocytosis-promoting factor), which interferes with immune cell function, contributes to ciliary damage, and aids attachment to respiratory epithelium; 3) filamentous hemagglutinin, which helps the bacteria attach to cilia of the respiratory tract; 4) pertactin (also called 69 kilodalton protein), which also aids bacterial attachment to cilia; and 5) agglutinogens, which may aid persistent attachment to cilia. Acellular vaccines were developed using one or more of these components (Table 2).

Vaccine efficacy. In studies Conducted in the United States, diphtheria and tetanus toxoids and pertussis vaccine (DTP) vaccination was found to be between 70% and 90% effective in preventing pertussis disease. (19,20) In studies conducted in Europe, diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) demonstrated efficacies between 59% and 89% and DTP vaccines had efficacies from 36% to 98% (see Table 2). (21-24) However, it is difficult to compare the results of various studies because of differences in 1) study type, 2) degree of blinding, 3) case definition of pertussis, 4) criteria for confirmation of pertussis infection, 5) ethnicity of study population, 6) number of children studied, 7) timing of the vaccine schedule, and 8) manufacturer of whole-cell vaccine used for comparison. Some of the DTaP and DTP vaccines studied in Europe are not available in the United States.

Currently, three vaccines are licensed in the United States: SKB-3P (Infanrix), CB-2 (Tripedia), and CLL-4F2 (DAPTACEL).

The protection afforded by pertussis vaccination wanes with time. For whole-cell (DTP) vaccines, protection against pertussis disease is lost by 12 years after the last dose.

Adverse reactions. DTaP vaccines have approximately one-quarter to one-half the common adverse reactions associated with whole-cell DTP vaccines, with similar rates for DTaP and DT (Table 3). (25-28) Minor adverse reactions associated with DTaP vaccination include localized edema at the injection site, fever, and fussiness.

Uncommon adverse reactions after whole-cell DTP are persistent crying for 3 or more hours following vaccination, an unusual high-pitched cry, seizures, and hypotonic-hyporesponsive episodes. (29) Most seizures that occur after DTP vaccination are simple febrile seizures that do not have any permanent sequelae. It is generally accepted that on rare occasions a child may have an anaphylactic reaction to DTP; in these cases further doses of DTP or DTaP are contraindicated. Allegations of other serious adverse reactions, such as permanent neurologic damage, after a dose of DTP vaccine are controversial and have been discussed elsewhere in depth. (30,31)

Administration of a DTaP vaccine has also been associated with seizures, persistent crying, and hypotonic-hyporesponsive episodes but at lower rates than after administration of a DTP vaccine. Rarely, temporary swelling of the entire limb (arm or leg) has occurred after administration of doses 4 or 5 of DTaP. Acellular pertussis vaccines currently produced in the United States have either no or trace thimerosal.

Recommendations

DTaP is recommended for all children because of the reduced risk of adverse reactions when compared with DTP. Whole-cell DTP is no longer recommended for use in the United States. Although five doses of pertussis vaccine are recommended, persons who receive their fourth dose on or after their fourth birthday do not need the fifth dose. Premature infants should be vaccinated with full doses at the appropriate chronological age (e.g., 2 months, 4 months, etc.). Full doses should be used because fractional doses are not as immunogenic as are full doses and might not lessen the risk of adverse reactions. The recommended series should be completed for optimal efficacy. One study based its case definition as a cough of at least 14 days with paroxysms, whoop, or vomiting. The investigators reported that the efficacy of whole-cell vaccine is 36% after 1 dose, 49% after 2 doses, and 83% after 3 doses. (32)

Other combination vaccines that include acellular pertussis vaccine are in development. The first combination licensed was TriHIBit, in which the Haemophilus influenzae type b (Hib) vaccine ActHIB is reconstituted with the Tripedia acellular pertussis vaccine. TriHIBit is currently licensed only for use as the fourth dose of the series and should not be used earlier unless so licensed.
SPECIAL TOPIC

Pertussis in adolescents
and adults

Although adults and adolescents are the primary
source of pertussis infection in young
infants, (33) their morbidity from pertussis is
low. Furthermore, the incidence of adverse
reactions after administration of whole-cell
pertussis vaccine to older children and adults
is relatively high; half of such individuals
who receive monovalent or combination
whole-cell pertussis vaccine develop induration
at the injection site. (34,35) Therefore,
whole-cell pertussis vaccine alone or in combination
with other vaccines is not indicated
for use in those older than 7 years. No acellular
vaccines have been licensed for use in
persons 7 years of age or older although
there is considerable interest in this.


DIPHTHERIA AND TETANUS TOXOIDS

Disease burden

Prior to widespread immunization, tetanus neonatorum caused hundreds of thousands of deaths worldwide. In comparison, only 26 cases of tetanus were reported in 2000 in the United States. Suffering also occurs due to spasm of the muscles of mastication, called trismus or lockjaw, and due to spasm of the back muscles (opisthotonos, color Figure 2).

[FIGURE 2 OMITTED]

In the 1920s, about 14,000 deaths due to diphtheria were reported annually in the United States, compared with only 2 cases in 2000. Complications included myocarditis, heart failure, and neuritis. The tonsils are one of the most common sites of infection (color Figure 3).

[FIGURE 3 OMITTED]

Recommendations

Adult tetanus and diphtheria toxoids (Td) are recommended for routine booster doses every 10 years for persons 7 years of age and older. Alternatively, boosters can be scheduled during adolescence and at age 50. (36) These boosters contain about the same quantity of tetanus toxoid as the DTP or pediatric DT vaccines but only one third to one-eleventh as much diphtheria toxoid.

Persons who experience an Arthrus-type hypersensitivity reaction or a fever of greater than 39.4[degrees]C (103[degrees]F) after a previous dose of tetanus toxoid probably have high serum antitoxin titers and should not receive a dose of Td more often than every 10 years. (19) The 2001 shortage of Td is over.

HAEMOPHILUS INFLUENZAE TYPE B VACCINES

Disease burden

Before the development of effective vaccines, Hib caused invasive disease in about 1 of every 200 children younger than 5 years of age in the United States. (37) It was the most common cause of bacterial meningitis in this age group, with a peak incidence between 6 and 12 months of age. Hib meningitis, the form taken by about two-thirds of cases of invasive Hib disease, carries a 2% to 5% mortality rate, even with appropriate treatment. Neurologic sequelae (including hearing loss, vision loss, mental retardation, seizures, and motor and speech delays) are seen in 15% to 30% of survivors. Other manifestations of invasive Hib disease include epiglottitis (with a 5% to 10% mortality rate due to airway obstruction), cellulitis (especially facial, periorbital, and orbital locations), pneumonia, osteomyelitis, septic arthritis, bacteremia, and pericarditis. (38)

Rationale for vaccination

Because of the high mortality and complication rates of even properly treated Hib disease, the need for a vaccine was apparent many years before a useful vaccine was developed. The Hib organism is encapsulated in a polysaccharide capsule. This capsule contributes to the virulence of Hib, and antibody directed against this polysaccharide provides protection against invasive disease. Haemophilus influenzae organisms that are unencapsulated commonly colonize the respiratory tract and cause sinusitis, otitis media, and bronchitis. Vaccines against Hib do not afford protection against these nontypeable strains or against non-b H influenzae (types a and c through f).

Vaccines. In 1985, the first Hib vaccine became available for use in the United States, a polysaccharide that is a purified form of the Hib capsule. Because infants' immune systems respond poorly to polysaccharide antigens, this vaccine was not approved for use in children under 18 months of age, the group at greatest risk of Hib disease.

To develop a vaccine immunogenic in infants, the polysaccharide antigen of the Hib capsule had to be linked to a protein that would improve recognition by the immature immune system.

The first of these so-called "conjugate" vaccines, ProHIBIT, linked Hib polysaccharide to diphtheria toxoid and was licensed in 1987, but again for children 18 months and older.

Since 1990, four additional Hib vaccines that are immunogenic in infants as young as 6 weeks of age have been licensed. HibTITER (HbOC) links Hib polysaccharide to a mutant diphtheria protein; ActHIB and OmniHIB (PRP-T) use tetanus toxoid; and PedvaxHIB (PRP-OMP) uses meningococcal group B outer membrane protein. (38) Conjugate Hib vaccines by themselves do not result in protection against the protein used in conjugation (i.e., PRP-T by itself does not protect against tetanus).

Hib vaccine should not be given before 6 weeks of age because it can induce immune tolerance to the antigen. This inhibits antibody formation and may increase the risk of disease.

Vaccine efficacy. Conjugate Hib vaccines are highly efficacious. Clinical efficacy has been estimated between 95% and 100%. Not only has the incidence of invasive Hib disease dropped by more than 99% since the introduction of conjugate vaccine, (39) but nasopharyngeal carriage rates have dropped in immunized children. This protects unimmunized children with whom they come in contact. (40)

Adverse reactions. No serious adverse reactions have been linked to Hib vaccine. Local reactions (tenderness, swelling, erythema) occur in 5% to 30% of recipients. Fever occurs in less than 5% of recipients. (38)

Recommendations

* All infants should be routinely immunized against Hib disease.

* Routine immunization should begin at 2 months of age, and no earlier than 6 weeks of age.

In general, unimmunized children have acquired natural immunity to invasive Hib disease by 5 years of age, either through asymptomatic colonization or through cross-reactive antibodies to other organisms. Therefore, routine Hib immunization of children 5 and older is not recommended. However, in some children, the risk of invasive disease is unusually high (e.g., anatomic or function al asplenia or immunocomproraised states), and these children should be immunized even after the fifth birthday, if their immunization has been delayed for some reason.

Disease in an immunized child. In the rare event that an immunized child develops Hib disease before the age of 24 months, a complete series of Hib vaccination should be started during the convalescent phase of the illness to help prevent subsequent Hib disease. These children clearly lack an adequate amount of protective antibody, and natural Hib disease does not reliably induce immunity in the very young.

PNEUMOCOCCAL CONJUGATE VACCINE

Disease burden

Streptococcus pneumoniae is a gram positive diplococci with a polysaccharide capsule that helps protect it from host defense mechanisms: 90 capsular serotypes have been identified.

Morbidity and mortality. S. pneumoniae causes approximately 2,600 cases of meningitis, 63,000 cases of bacteremia, 100,000 to 135,000 cases of pneumonia requiring hospitalization, and 7 million cases of otitis media annually in the United States. (41)

Among children younger than 5 years of age, S. pneumoniae annually causes about 17,000 cases of invasive disease, including 200 deaths. (42) The incidence rates are highest in infancy, decline with age, and then increase in the elderly (Table 4).

Invasive disease consists of bacteremia, meningitis, or infection in a normally sterile site, excluding the middle ear. S. pneumoniae is the most common bacterial cause of community-acquired pneumonia, sinusitis, and acute otitis media in young children. (42) Because of the tremendous success of Hib vaccines in reducing Hib meningitis, S. pneumoniae now has become the leading cause of bacterial meningitis in the United States. (43)

Route of transmission. Infection is spread by droplets from respiratory tract secretions.

Rationale for vaccination

Risk factors. Risk factors for invasive pneumococcal disease include age, race, recent use of antibiotics, attendance at daycare, exposure to tobacco smoke, and chronic medical conditions.

Compared with Caucasians, rates of infection for African Americans are about twofold to threefold higher; Alaskan Natives and Native Americans have about a threefold to sevenfold higher risk (Table 4).

Children with sickle-cell disease have high rates of disease; penicillin prophylaxis reduces the risk fur pneumococcal disease in sickle-cell disease, but the rates are still elevated at about 1,350 per 100,000 persons. (42)

Other predisposing risk factors include other sickle hemoglobinopathies, functional or anatomic asplenia, infection with human immunodeficiency virus (e.g., 9,000 per 100,000 in HIV-infected children; see Table 4), recent antibiotic treatment, and passive smoking. (44,45)

Out-of-home daycare increases the risk for invasive pneumococcal disease by twofold to threefold and the risk for penicillin resistance as well. (44) Breast-feeding is protective. (44-46)

Resistance to antibiotics. Heightening the importance of immunizations is the increasing proportion of S. pneumoniae that are resistant to antibiotics. In 1998, based on cases of invasive pneumococcal disease detected in the surveillance areas for the Active Bacterial Core, fully 24% of isolates had intermediate susceptibility or were resist ant to penicillin. (41) Some isolates are resistant to multiple antibiotics. (47)

Polysaccharide and conjugate pneumococcal vaccines. Two vaccines are currently available against pneumococcus: the older 23-valent polysaccharide vaccine (Pneumovax 23) and the 7-valent conjugate (Prevnar) vaccine licensed in 2000.

The older pneumococcal polysaccharide vaccine contains T-independent antigens that stimulate mature B-lymphocytes to produce effective antibody but not T-lymphocytes. Thus, T-independent immune responses do not produce an anamnestic response upon challenge and may not be long-lasting.

The vaccine is effective among older children and adults but not in children less than 2 years of age, as they do not respond well to such antigens. In tact, the serotypes that cause the majority of disease (i.e., 6A, 14, 19F, and 23F) do not induce a good immune response to polysaccharide vaccine until 5 years of age. (48) Finally, the polysaccharide vaccine does not reduce nasopharyngeal colonization of S. pneumoniae, although the importance of this is debated.

A 7-valent immunogenic pneumococcal conjugate vaccine, PCV, was licensed in 2000 in the United States. (49,50) The carrier protein is CRM-197, which has been used in one Hib vaccine. PCV does not contain thimerosal. The vaccine was designed to cover the seven serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) most common in children. These serotypes account for about 80% of invasive infections in children younger than 6 years of age, but only 50% of infections in those aged 6 and older (Figure 1). (51) Obviously, PCV covers fewer serotypes than the 23-valent polysaccharide vaccine. However, among the serotypes in PCV, it is more immunogenic than the polysaccharide vaccine. The PCV also elicits a T-dependent immune response that leads to anamnestic response on challenge and is effective in infants. It also reduces nasopharyngeal carriage of S. pneumoniae and theoretically could create herd immunity, based on experience with Hib vaccine.

PCV vaccine efficacy. A randomized, double-blind controlled trial was conducted at Northern Kaiser Permanente, California, from 1995 to 1998. In the primary efficacy analysis, the effectiveness against invasive disease was 100%.

In the follow-up analysis done 8 months later, the efficacy against invasive disease in the intention-to-treat analysis was 94% lot serotypes included in the vaccine; among the fully vaccinated, it was 97% for serotypes in the vaccine. (52) The efficacy against all serotypes including non-vaccine types was 89%, suggesting some cross-protection among related serotypes. (52)

In the intention-to-treat analyses, which are clinically more meaningful, the efficacy was 11% against clinical pneumonia, 33% against clinical pneumonia supported with any radiographic evidence of infiltrate, and 73% against pneumonia with radiographic evidence of consolidation [greater than or equal to] 2.5 cm. Of course, radiographic evidence of consolidation is more typical of pneumococcal pneumonia, whereas clinically diagnosed pneumonia is often viral. (52) The vaccine also reduced ventilatory tube placement by 20.1% and antibiotic use by 5.3%.

The number needed to vaccinate ("treat") is 411 to prevent an episode of invasive disease, 239 to prevent pneumonia, and 151 to prevent invasive disease or pneumonia.

Published analyses show that the vaccination of healthy infants would prevent more than 12,000 cases of meningitis and bacteremia and 53,000 cases of pneumonia. (53) The break-even price for PCV is $46 per dose from the societal perspective and $18 per dose from the health-care payer's perspective. (53) Infant vaccination costs $80,000 per year of lilt saved and $3,200 per pneumonia case prevented. The manufacturer's list price is about $58 per dose, making it the most expensive routine infant immunization series to date. Actual prices vary by setting.

Adverse reactions. No serious adverse reactions are associated with PCV. When given with DTaP but at another site, fever [greater than or equal to] 38[degrees]C occurred in 15% to 24% of those vaccinated with PCV corn pared with 9% to 17% of those receiving the control vaccine (experimental meningococcal conjugate vaccine). (52) Among PCV vaccinees, 10% to 14% develop redness at the injection site and 15% to 23% develop tenderness at the injection site. (52) Fever greater than 39[degrees]C was uncommon, occurring in 1% to 2.5% of vaccinees.

Recommendations

After PCV was licensed by the Food and Drug Administration, three organizations recommended its use: the ACIP at the Centers for Disease Control and Prevention (CDC), the AAP, and the AAFP. (42,54,55)

All recommend PCV for routine infant immunization and catch up vaccination of children aged [less than or equal to] 23 months; 23 months was chosen as the end for routine catch up vaccination for all healthy children because:

* The incidence rate of invasive disease drops substantially by age 24 months (Table 4).

* By 2 years of age children have a more mature immune system and are better able to withstand pneumococcal infection than younger children.

* The cost of the vaccine is substantial when compared with other childhood immunization series and, given limited resources in some situations, the priority should be with those at highest risk.

The ACIP, AAP, and AAFP all recommend catch-up vaccination of children 24 to 59 months of age at high risk for invasive disease, including those with sickle cell disease, asplenia, HIV infection, chronic illness (e.g., bronchopulmonary dysplasia. congenital heart disease, congestive heart failure, diabetes mellitus, and cerebrospinal fluid leaks), immunocompromising conditions including con genital immune or complement deficiencies, renal failure, nephrotic syndrome, and malignancies or other conditions treated with immunosuppressive therapy or radiation therapy (e.g., solid organ transplantation). Penicillin prophylaxis should continue for children with sickle cell disease after vaccination with PCV.

These organizations vary in their recommendations for catch-up vaccination of healthy children 24 to 59 months of age. The incidence rates decrease during childhood; the case [or several different cut-off points can be made.

Decision-making may be helped by evaluating individual risk factors for invasive pneumococcal disease, such as attendance at daycare, passive smoking, and race.

Consistent with the data for increased risk by race (Table 4), the AAFP recommends catch-up vaccination of children 24 to 59 months who are of Alaska Native, American Indian, and African American descent; the ACIP and AAP state that vaccination can be considered R)r these groups. The AAFP regards vaccination as an option for children aged 24 to 59 months who attend childcare settings or have had frequent or complicated acute otitis media in the previous year.

PCV is not licensed for use in adults. No efficacy data are available for older children and adults. Because the serotypes change with age, only about 50% of the serotypes that cause infection in older children and adults are covered by PCV, in comparison to 80% to 90% for 23-valent pneumococcal polysaccharide vaccine (Figure 1). Although the ACIP and AAP allow use of PCV in older children who have high risk conditions, it should not replace the polysaccharide vaccine in older children or adults.

POLIOVIRUS VACCINE

Disease burden

Poliomyelitis was a dreaded disease in the 20th century (color Figure 4). Over 18,000 paralytic cases occurred in 1954 in the United States (Table 1). A recent outbreak of poliomyelitis in the Dominican Republic and Haiti was due to a revertant virus (i.e., mutated so no longer attenuated) from oral poliovirus vaccine strain 1. It demonstrates the need for continued vigilance to maintain high rates of vaccination. Poliovirus is an enterovirus that occurs in three serotypes. The virus is quite infectious, and transmission to susceptible household contacts occurs in 73% to 96% of infections, depending on the contact's age.

[FIGURE 4 OMITTED]

Morbidity and mortality. The results of poliovirus infection, in decreasing order of likelihood, are subclinical infection (up to 95% of cases), nonspecific viral illnesses with complete recovery (about 5% of cases), nonparalytic aseptic meningitis (1% to 2% of cases), and paralytic poliomyelitis (less than 2% of cases). (19) The ratio of inapparent to paralytic illness is about 200:1 (range 50:1 to 1,000:1). (19) The case-fatality rate of paralytic polio is 2% to 5% in children and 15% to 30% in adults.

Route of transmission. Transmission occurs primarily by the fecal-oral route, although oral-oral transmission can occur. After the virus enters the mouth, it multiplies in the pharynx and gastrointestinal tract before invading the bloodstream and, potentially, the central nervous system. The incubation period ranges from 3 to 35 days. (19)

Rationale for vaccination

Poliovirus vaccination programs have resulted in dramatic decreases in disease incidence. Circulation of indigenous wild polioviruses ceased in the United States in the 1960s (56); the last case of wild poliomyelitis contracted in the United States was reported in 1979. In 1991, the last case of poliomyelitis due to indigenous virus in the Americas occurred in Peru; in 1994, the Americas were declared free of indigenous poliomyelitis. (57,58)

Vaccines. Two vaccines have been used in the United States: inactivated poliovirus vaccine (IPV) and oral poliovirus vaccine (OPV).

Inactivated poliovirus vaccine (IPV), also known as the Salk vaccine, was licensed in 1955. An enhanced-potency IPV formulation became available in 1988 and is the IPV in use in the United States today. It is inactivated and cannot cause vaccine-associated paralytic poliomyelitis (VAPP). Thus, it is safe for immunocompromised persons and their contacts. Its disadvantages include administration by injection and less gastrointestinal immunity.

Oral poliovirus vaccine offers easier administration and induces early intestinal immunity. Its main disadvantage is that it can revert to a more virulent form and cause VAPP.

Adverse reactions. The overall risk of VAPP from OPV is quite small: between 1980 and 1994, 303 million doses of OPV were distributed. A total of 125 cases of VAPP were reported for a risk of 1 case per 2.4 million doses of OPV. (19) Healthy vaccine recipients had 49 cases, usually after the first dose of vaccine (1 case per 750,000 first doses); healthy contacts of vaccine recipients, 40 cases; immuno-deficient vaccine recipients, 23 cases; and immunodeficient contacts of vaccine recipients, 7 cases. In 6 other cases, VAPP was community acquired. (19)

The rationale for transition to the all-IPV schedule is

* Exposure to indigenous wild poliovirus in the United States has ceased and widespread circulation of indigenous wild polioviruses ceased in the 1960s.

* OPV has a slight risk of VAPP whereas IPV does not cause any serious reactions.

* The majority (61%) of parents prefer to have their child undergo more injections rather than face the risk of VAPP. (59)

* Data show 91% acceptance of an IPV-starting schedule among parents who bring their children to public health vaccine clinics, including those serving inner-city disadvantaged areas. No decrease in immunization rates have been seen, although this had been a major concern in switching to a schedule with IPV. (60)

* Clinicians find it easier to administer and store one vaccine rather than explaining the choices and stocking two vaccines.

Poliovirus vaccination continues to be recommended because of outbreaks in other countries, ease of importation of wild virus, and the highly contagious nature of the virus.

Recommendations

The all-IPV schedule is recommended for the United States. OPV is no longer recommended in the United States, but it is recommended by the World Health Organization for global eradication efforts. It provides the earliest mucosal immunity.

Prior to school entry, four doses of poliovirus vaccine are generally recommended; any combination of IPV and/or OPV is acceptable.

MEASLES, MUMPS, AND RUBELLA VACCINE (MMR)

Disease burden

Through the 20th century, the burden of disease due to measles, mumps, and rubella ("German measles") has declined dramatically because of widespread vaccination against these three viruses. (61) In 2001, in the the United States, the annual reported cases dropped from earlier peaks of 503,000 to 116 for measles, 152,000 to 266 for mumps, and 50,000 to 23 for rubella. (61,62)

Characteristics. The characteristic rash of measles, which appears about 14 days after exposure, is preceded by cough, coryza, conjunctivitis, and, sometimes, Koplik's spots on the buccal muscosa (color Figures 5 and 6).

[FIGURES 5-6 OMITTED]

Measles can be severe with high fever and prostration, sometimes acutely fatal, or it can be complicated by a delayed fatal encephalopathy, usually with onset in early adolescence. Mumps produces excruciating bilateral parotitis (color Figure 7) and sometimes complicated pancreatitis, orchitis. cerebellar ataxia, or death. In contrast, rubella usually causes only posterior cervical adenopathy and minimal rash (color Figure 8), but it can produce devastating fetal infection.

[FIGURES 7-8 OMITTED]

Epidemiology. Although the vaccines for these three viruses are extraordinarily effective in preventing these infections, (61,63,64) occasional outbreaks of all three illnesses are reported in the United States, including a 1989 to 1991 measles epidemic. Outbreaks of rubella occurred from 1994 to 1997, particularly among those aged [greater than or equal to] 20 years, who were generally unimmunized persons in prisons, colleges, office buildings, or medical workplaces, who comprised 65% of all cases.

Measles cases are most frequently imported. Outbreaks occur because measles is highly contagions, with an attack rate among unvaccinated household contacts of 90% or higher. Infected persons may transmit the disease from 4 days before to 4 days after the appearance of the rash.

Rationale for vaccination

Vaccine. The measles, mumps, rubella (MMR) vaccine is a successful combination of three live, attenuated viruses. Individual vaccine or any combination of vaccines is available, but combinations with varicella vaccine have yet to be approved. (61)

Each vaccine contains neomycin, gelatin, sorbitol, and human albumin, all potential allergens. Measles and mumps vaccines are produced in chick cells, and rubella in human cells. The measles vaccine currently used in the United States (the Edmonston-Enders strain) contains live, highly attenuated virus.

Although efficacy is high, two factors may con tribute to inadequate protection from the first dose of measles vaccine: 1) lack of initial seroconversion, usually due to the presence of higher initial titers of maternally acquired antibody, and 2) waning immunity.

Mothers whose immunity is acquired actively rather than passively (by vaccination) confer higher initial levels of immunity to their infants, who then have protective antibody levels until about 11 months of age. As a result, seroconversion rates are optimal when administration of MMR vaccine is delayed until children are 15 months of age. Because maternal immunity to measles is now primarily due to vaccination, the duration of immunity transferred to infants is decreased to about 9 months of age, making vaccination at 12 months of age ideal. This change probably accounts for the fact that, in 1990, 26% of measles cases occurred in children <16 months of age whose immunity was inadequate, possibly due to waning antibody levels. In response to these findings, the current ACIP recommendation for the first dose of MMR is lot 12 to 15 months of age. (61)

Failure of seroconversion after the initial dose of measles vaccine occurs at a rate of 2% to 5%. In comparison, the rate of secondary vaccine failure (waning immunity) is less than 0.2%. (61)

Vaccine efficacy. Following measles vaccination, seroconversion rates are 95% for children vaccinated at 12 months of age and 98% for children vaccinated at 15 months of age. (61) Antibody persists for at least 17 years and probably throughout life in almost all vaccinated persons who initially sero-convert. Of the few whose antibody level wanes, most are probably still immune, as demonstrated by secondary immune responses upon revaccination. After two doses, more than 99% of persons are immune. Vaccination of already immune individuals is not harmful.

Adverse reactions. Pain, irritation, and redness at the site of injection are common but mild. Delayed reactions to measles vaccine include fever, usually below 38.8[degrees]C (102[degrees]F), or rash that occurs 5 to 20 days later and lasts for 2 to 5 days. Measles vaccine does not cause autism. (61)

Adverse reactions to rubella vaccine include generalized lymphadenopathy in children and arthralgia in young women, with no proven long term arthritis.

Adverse reactions to mumps vaccine include transient orchitis in young men. Rarely, thrombocytopenia has been reported due to the rubella component. (30) Some physicians report "arm syndrome" (brachial neuritis) or "'catcher's crouch" (lumbar radiculoneuritis) as potential adverse reactions (65) but reviews by the Institute of Medicine revealed either no evidence, in the case of mumps vaccines, or insufficient evidence, in the case of measles and rubella vaccines, for such allegations. (30,66)

Recommendations

The MMR vaccine is routinely given to all healthy children at age 12 to 15 months. A second close is administered at age 4 to 6 years. A second dose is especially important for military recruits, college students, and susceptible health-care personnel (see "Vaccines for Persons at High Risk Due to Medical Conditions, Occupation, Environment, or Lifestyle, 2003").

Persons born before 1957 are assumed to have had measles and mumps, but they should not be assumed to be immune to rubella. The latter must be proven via serum antibody tests (especially for women of child-bearing age) or be induced by vaccination. (61) Assurance of immunity by either vaccination or testing is especially important for unimmunized immigrants.

Persons who received killed measles vaccine--used in 1963 to 1967--or an unknown type of measles vaccine--used between 1963 and 1967--should receive two doses of live measles vaccine. Persons who received measles vaccine along with either immune globulin or measles immune globulin should be considered susceptible and be revaccinated with at least one close of measles vaccine unless the measles vaccine type is known to be Edmonston B. MMR is preferred over giving its components separately.

If antibody or blood products including RhoGAM are given before MMR, a sufficient interval must pass alter the date of receiving the antibody or blood products before administering the MMR or the vaccine may not be effective. The amount and type of product will determine the interval (at least 3 months but up to 9 months, depending on the product) necessary before MMR vaccination. (61,67)
SPECIAL TOPIC

Special situations: measles
outbreaks, postexposure
prophylaxis, and treatment

MMR or measles vaccine may be given for
epidemic control as early as 6 months of age,
but this does not count as the first dose of
vaccine; two additional doses of MMR must
be given later as routinely scheduled.

Unvaccinated persons 12 months of age
and older who are exposed to measles
should be given measles vaccine (usually as
MMR) if it can be administered within 72
hours of exposure. Immunoglobulin may be
used to control measles for exposed
immunocompromised persons, 0.25 mL/kg/
dose (max 15 mL) given IM within 6 days of
exposure. Vitamin A therapy reduces
measles morbidity and mortality. (61)


VARICELLA VACCINE

Disease burden

During childhood, the highly contagious varicella-zoster virus (VZV) most often causes chickenpox, which is generally a self-limited and benign illness (color Figure 9). Prior to varicella vaccine, roughly 4 million cases of VZV infection occurred annually in the United States with a hospitalization rate of 5 cases per 1,000 population and a death rate of. 0.7 per 100,000. (68) Because secondary attack rates are as high as 90% and because communicability by aerosol droplet begins 1 to 2 days prior to the rash, prevention of spread requires a universal vaccination program.

[FIGURE 9 OMITTED]

Complications. Complications include secondary bacterial skin infection (both impetigo and invasive group A streptococcal disease), pneumonia, Reye syndrome (now rare), encephalomeningitis, glomerulonephritis, thrombocytopenia, purpura fulminans, cerebellar ataxia, arthritis, and hepatitis. (69) Although neonates are only rarely afflicted with the congenital varicella syndrome (limb atrophy and scarred skin), the threat of neonatal sepsis is present for those whose mothers are not immune to VZV and who develop VZV 5 days before to 2 clays after delivery. The lifetime risk of the late complication of herpes zoster (shingles) is 10%.

Rationale for vaccination

VZV is most severe in neonates and in adults; hospitalization rates are 103 and 65 per 10,000 cases, respectively. The rate is 23 per 10,000 in children aged 1 to 4 years; however, the majority of annual hospitalizations occur in the 1 to 4 age group because VZV is so common at those ages. (70) Most hospitalized individuals are immunologically normal but many develop the secondary complications mentioned above, sometimes with fatal outcomes. Additional factors favoring a universal vaccine program include the cost of lost time from work or school and the burden of disease suffering.

Routine vaccination is a cost-effective measure to reduce VZV morbidity and mortality. (71) Each dollar spent on universal immunization of children avoids approximately $5 in costs. (71)

Vaccine and vaccine efficacy. The current varicella vaccine contains live attenuated virus (Oka strain) and is 97% effective against moderately severe and severe disease and 85% protective for any infection for at least 7 years. (72) In vaccinees, disease is mild, with fewer than 30 pox lesions. (73)

Because varicella vaccine is less immunogenic in older children and adults, a second dose is required in those aged 13 years and older. The seroconversion rate in these individuals is 67% to 85% after one dose and 94% to 100% after the second dose, given d to 8 weeks later.

The long-term duration of vaccine-induced immunity is unknown. The concern remains unresolved as to whether widespread vaccination of children would shift the disease burden to adults with waning antibody levels. One expert panel estimated that a child given one dose of varicella vaccine might have a 15% chance of eventual inadequate immunity over a lifetime. (74) Furthermore, repeated exposure to wild varicella in the community should--at least in the immediate future--boost antibody levels. Continued surveillance of vaccine-induced antibody levels is in progress. Protective antibody levels have persisted for longer than 20 years in Japan. (75)

Although booster doses may eventually be required, mathematical models show that even if the disease peak shifted to adults, the overall hospitalization number and mortality would drop with immunization, even if immunity fails more rapidly than expected. (68) Thus, the overall decrease in hospitalization and severe disease favors universal childhood vaccination.

Adverse reactions. Local pain and erythema occur in 2% to 20% of children and 10% to 25% of adults after the first dose. Up to 47% develop local reactions with the second dose. From 4% to 10% develop a few (median of 5) varicella-like lesions 5 to 41 days after administration that last 2 to 8 days. Low-grade fever develops up to 42 days later in 12% to 30% of vaccinees. Its duration is brief. Vaccine virus has been rarely transmitted to healthy immunocompetent siblings and parents, especially if the vaccinee developed a varicelliform rash or had leukemia. No major ill effects have resulted. Rare hypersensitivity reactions to gelatin or neomycin are possible. Those with previously unrecognized VZV infection or prior immunization are not at increased risk. To date, the risk lot zoster is less among vaccinees than those who had natural infection.

Recommendations

The ACIP, AAFP, and AAP recommend that children ages 12 months to the 13th birthday be given one dose unless they have a history of prior varicella infection. Vaccine is also recommended for adolescents ([greater than or equal to] 13 years of age) and adults without a history of chickenpox on a two-dose schedule spaced 4 to 8 weeks apart. Adults should be assessed for immunity to varicella, beginning with the question, "Have you had varicella?" (76) Because about 70% to 90% of those without a history of chickenpox are actually immune, serologic tests may be cost-efficient, but they are not required because the vaccine is well tolerated in these individuals. Testing may make the most sense in 9- to 12-year-old children with uncertain VZV histories who are often already immune. Post vaccination serologic testing is unnecessary.

For adults without a history of chickenpox, the highest risk is lot those who live or work in settings where natural VZV is prevalent or transmission can occur: preschool, church school, or elementary teachers; childcare staff'; residents and staff in institutions for the developmentally delayed and correctional facilities; military personnel; college students: nonpregnant women of child bearing age; international travelers; adolescents and adults living with young children; medical personnel; and family contacts of immunocompromised persons.

Households with immunocompromised persons require no special precautions unless the vaccinee develops a rash, after which direct contact should be avoided. Immunocompromised contacts who develop a rash may require antiviral therapy.
SPECIAL TOPIC

Postexposure prophylaxis

Varicella vaccine is effective in preventing or
modifying varicella if given within 3 days
(and possibly up to 5 days) of exposure to
wild varicella. (77-79) Varicella-zoster immune
globulin (VZIG) is indicated lot exposed
immunosuppressed patients, during early
pregnancy for susceptible exposed mothers,
and for infants of mothers who develop
chickenpox 5 days before to 2 days after
delivery at 125 units/10 kg (max 625 U; min
125 U). It should ideally be given IM within
96 hours of exposure.


HEPATITIS A VACCINE

Disease burden

Hepatitis A is one of the most common vaccine-preventable diseases in the United States.

Incidence and prevalence. The reported incidence of hepatitis A is highest among children 5 to 14 years of age; approximately one-third of reported cases involve children under 15 years of age. (80) Many more children have unrecognized infection and can be the source of infection for others. Hepatitis A incidence varies by race/ethnicity. The highest rates are found among Native Americans/Alaskan Natives and the lowest rates among Asians. Rates among Hispanics are higher than among non-Hispanics. (80) These disparities most likely reflect differences in the risk for infection related to factors such as socioeconomic levels and living conditions, as well as more frequent contact with persons from countries where hepatitis A is endemic.

Route of transmission. Hepatitis A virus infection is acquired primarily by the fecal-oral route through either person-to-person contact or ingestion of contaminated food or water. Depending on conditions, the virus can be stable in the environment for months. (81) On rare occasions, the virus has been transmitted by transfusion of blood or blood products. (82)

The most frequently reported source of infection, occurring in 12% to 26%, is either household or sexual contact with a person with hepatitis A. (83,84) International travelers, especially to Mexico, account for an additional 4% to 6% of the infections. Only 2% to 3% of cases are associated with recognized food or waterborne disease outbreaks. (83,84) Most persons with hepatitis A have an unidentified source for their infection. (83,84)

Characteristics and mortality. Hepatitis A virus is a picornavirus that causes infections in humans after an incubation period of 28 days. It can be either asymptomatic or symptomatic. (85) In its classic form, the illness has an abrupt onset of symptoms, including fever, nausea, anorexia, malaise, and jaundice. Most infections in children younger than age 6 are asymptomatic, (86) In contrast, infections in adults are symptomatic; 70% of adults develop jaundice. (87) The illness is usually self-limited and lasts less than 2 months, although an estimated 100 persons die as a result of acute liver failure resulting from hepatitis A each year. Although only 0.3% of all patients with acute hepatitis A develop fulminant hepatitis A, the rate is 1.8% among adults over 50 years of age. (80) Persons with chronic liver disease are at increased risk for fulminant hepatitis A. (88)

Rationale for vaccination

Hepatitis A vaccine. Both licensed vaccines are highly immunogenic in children aged 2 to 18 years and in adults. Protective antibody levels developed in 94% to 100% of people 1 month after the first dose and essentially 100% after the second dose. (89,90) Available data indicate that hepatitis A vaccine is immunogenic in children under 2 years of age who do not have passively acquired maternal antibodies. Two doses of vaccine are recommended.

Vaccine efficacy. The efficacy of the hepatitis A vaccine is between 94% and 100%. Duration of protection has been evaluated in several studies; in both adults and children protection has been demonstrated for at least 6 to 8 years. (91,92) Estimates of antibody persistence derived from kinetic models of antibody decline indicate that protection could persist for greater than 20 years. (93)

Adverse reaction& The most frequently reported side effects included soreness at the injection site, warmth at the injection site, and headache. Follow up of over 5 years regarding adverse events from an estimated 65 million doses of hepatitis A vaccine administered worldwide among children and adults did not find any serious adverse events that could definitely be attributed to hepatitis A vaccine.

Recommendations

The ACIP 1996 recommendations on the prevention of hepatitis A focused primarily on vaccinating persons in groups shown to be at high risk for infection (e.g., travelers to countries with high or intermediate disease endemicity, men who have sex with men, injection drug users, and persons with clotting-factor disorders), persons with chronic liver disease, and children living in communities with high rates of disease.

In October 1999, the ACIP added recommendations tot routine vaccination of children in states, counties, or communities with rates twice the 1987 to 1997 national range or greater (i.e., [greater than or equal to] 20 cases per 100,000 population). Consideration should be given to routine vaccination of children in states, counties, or communities with rates exceeding the 1987 to 1997 national average (i.e., greater than 10 but less than 20 cases per 100,000 population), (80) The CDC maintains a map with hepatitis A rates at www.cdc.gov/ncidod/diseases/hepatitis/a/vax/ index.htm.

INFLUENZA VACCINE

Disease burden

Taken together, influenza and pneumonia are the seventh leading cause of death nationally and the fifth leading cause in older adults. Influenza outbreaks of varying severity occur every winter.

Mortality and morbidity. Each year, influenza causes about 20,000 deaths; the figure climbs to 40,000 or more excess deaths in selected epidemics. (94)

The fatality rate from influenza begins to rise in mid-life and is highest in persons who have chronic medical conditions, such as chronic obstructive lung disease, cardiovascular disease, and diabetes mellitus, particularly the elderly. Due in part to a high rate of chronic medical conditions, the elderly are the population with the highest age specific case-fatality rate from influenza. They account for 90% or more of deaths; however, influenza has a higher case-fatality rate in middle aged persons with multiple chronic medical conditions than in healthy persons [greater than or equal to] 65 years of age. Data from the National Health Interview Survey show that fully 24% to 32% of those aged 50 through 64 have an underlying medical condition that places them at high risk for complications from influenza. (94)

Each year an average of about 114,000 excess influenza related hospitalizations occur; this figure climbs to over 300,000 in selected epidemics. (94,95) During the influenza season, hospitalizations increase as a result of pneumonia, acute bronchitis, chronic respiratory disease, and congestive heart failure. Among children aged 0 to 2 years, Neuzil et al found that influenza-related hospitalization rates range from about 800 to 1,900 per 100,000 for those with high risk conditions, to 186 to 1,038 per 100,000 for healthy children, depending on exact age. (94,96,97) Izurieta and colleagues found rates of 144 to 187 per 100,000 children aged 0 to 23 months. (94,98) Age-specific hospitalization rates are highest among preschoolers, especially infants aged 0 to 1 years, low-income persons, and the elderly. (96,98,99) Furthermore, one study showed that healthy children aged 6 months to <3 years had rates of influenza-associated hospitalization as high or higher than rates among children aged 3 to 14 years with high-risk conditions. (96,97) In one study, influenza was secondary only to respiratory syncytial virus (RSV) in causing hospitalizations in persons with chronic underlying illness. (99) Neuzil et al found that, for every 100 children, an annual average of 6 to 15 outpatient visits and three to nine courses of antibiotics were attributable to influenza. (96)

Complications. The complications of influenza are secondary bacterial pneumonia, worsening of chronic respiratory and cardiac diseases, sinusitis, and otitis media. (100) Primary viral pneumonia is uncommon. Reye syndrome is rare and is associated with salicylate use concomitant with influenza type A or B infection in children. Based on data from the Tecumseh Community Health Study, an estimated 13.8 to 16 million influenza-related excess respiratory illnesses occur annually in per sons less than 20 years of age. (101)

Route of transmission. Influenza is extremely contagious, usually transmitted from person to person by the airborne route. Consequently, persons in semi-closed or crowded environments, such as students, prisoners, and residents of nursing homes, are at high risk of exposure. In nursing homes, up to 60% of patients can develop disease. (102,103) Of those, 30% die. (104) Infected persons are most contagious during the period of peak symptoms. The incubation period is usually 2 days (range 1 to 4 days).

In contrast to the case-fatality rate, the illness attack rate is highest in children at 14% to 40% yearly with attack rates often over 30% in preschool-aged children. (101,105,106) Transmission in schools plays a major role in propagating influenza outbreaks, as seen by the rapid rise in student cases following holiday recesses. (107) Children frequently infect their families, as suggested by the increase in school absenteeism just prior to a noted increase in absenteeism among manufacturing employees and by the higher risk of infection for families with children than those without children. (107) Another indication of the importance of children in transmitting influenza is the success of a vaccination program that targeted grade school and high school children in order to limit an out break in an entire community. (108) Similarly, a Russian study showed that influenza vaccination rates in schools were inversely related to illness rates among staff and unvaccinated children. (109) A recent Japanese study showed that vaccination of school children reduced deaths among the elderly by 37,000 to 49,000 annually. (110)

Antigenic changes. Influenza is caused by infection with influenza types A or B. Influenza surface antigens periodically change, leading to antigenic shift and drift. Antigenic shift is a major change in the subtypes and occurs in influenza type A only. A shift results in a new strain to which little or no prior immunity exists. Subsequently, a pandemic (worldwide epidemic) usually features high attack rates in all age groups. Minor changes in the antigenic types are called antigenic drift and occur on a regular basis. Antigenic drill call occur for both types A and B. Changes resulting from drift are classified by designating prototype viruses such as A/Texas/36/91.

Rationale for vaccination

Although many persons aged 50 to 64 have a high risk condition such as asthma, diabetes mellitus, or heart disease, only a minority are vaccinated despite recommendations, as evidenced by data from the 2000 National Health Interview Survey showing that only 32% of those aged 50 through 64 who are at high risk for complications from influenza were vaccinated.

Manual or computerized reminder systems based on high-risk conditions are more difficult to implement than those based on age. Many persons with a high-risk condition are unaware of their risk; high-risk vaccination strategies for other immunizations have had limited success. After considering these factors, the burden of influenza disease, and the cost-effectiveness of vaccination, in 1999 the AAFP lowered the age for annual, routine influenza vaccination to age 50. The ACIP also recommends routine vaccination beginning at age 50 years.

Based on hospitalization rates due to influenza in young children, the efficacy of vaccination in reducing hospitalizations, illness episodes, and visits to physicians, and the safety of vaccination, the ACIP encouraged vaccination of healthy children aged 6 through 23 months, beginning ill the fall of 2002. A full recommendation (which is expected within the next 1 to 2 years) to annually vaccinate all children 6 to 23 months is hindered by the need to resolve issues of parent and clinician education, payments, and efficient delivery mechanisms of influenza vaccine to young children.

Influenza vaccine. The influenza vaccines currently licensed contain inactivated (killed) virus. The effectiveness of influenza vaccine in preventing or attenuating illness varies, depending primarily on 1) the degree of similarity between the virus strains included in the vaccine and those that circulate during the influenza season, and 2) the age and immunocompetence of the vaccine recipient. When a good match exists between vaccine and circulating viruses, influenza vaccine has been shown to prevent illness in about 70% to 90% of healthy persons less than 65 years of age. When the match between vaccine and circulating virus is poor, efficacy is less.

A study in Minnesota of working adults aged 18 to 64 years of age showed that influenza vaccination reduced episodes of upper respiratory illness (URI) by 25% (105 vs. 140 episodes per 100 subjects, number needed to treat to prevent 1 URI is 2.9), reduces sick leave from work due to URI by 43% (70 vs. 122 days per 1(10 subjects), and reduces visits to physicians' offices for URI by 44% (31 vs. 55 visits per 100 subjects; number needed to treat is 4.2 to prevent 1 physician visit). (111)

Elderly persons and those with certain chronic diseases may develop lower postvaccination antibody liters than healthy young adults, and thus may remain susceptible to influenza illness. Even if influenza illness develops despite vaccination, the vaccine lowers the risk of severe disease and complications in elderly persons in nursing homes and in the community at large. Among elderly persons in nursing homes, influenza vaccine efficacy in preventing influenza illness can be between 30% and 40%, in preventing hospitalization and pneumonia between 50% and 60%, and in preventing death [greater than or equal to] 80%. Achieving a high rate of vaccination among nursing home residents can reduce the spread of infections in a facility, thus preventing disease through herd immunity. Among elderly persons in the community during the influenza season, the effectiveness of influenza vaccine in preventing hospitalization for all causes of pneumonia and influenza ranges from 30% to 70%. (59,112-117) Furthermore, in one study, influenza vaccination resulted in a 37% reduction in hospitalization due to congestive heart failure and was 54% effective in reducing mortality from all causes. (117)

Immunity from influenza vaccine wanes following vaccination. Hence, annual vaccination just prior to the influenza season is recommended. It may take up to 2 weeks after vaccination for protection to develop.

Cost-effectiveness of influenza vaccine. In noninstitutionalized elderly adults, influenza vaccination has been shown to reduce the cost of hospitalization due to acute and chronic respiratory disease and congestive heart failure, and result in a direct savings of $117 per vaccince per year. (118) Other studies estimated the cost at $13 per year of healthy life gained (118) and $145 per year of life gained. (119) Meltzer and colleagues concluded that vaccinating healthy, low risk children was cost effective only when vaccine cost was low. Vaccinating high-risk children was more cost effective. (120) Other studies of preschool and school-aged children also concluded that influenza vaccination of these groups can be cost effective, especially if parents did not have to miss work time to have their children vaccinated, as in group-based or walk in flu vaccine clinics. (121-123)

Adverse reactions. Influenza vaccine can cause local reactions such as soreness at the injection site. In persons previously exposed to influenza disease or vaccination, placebo-controlled studies show similar rates of systemic reactions such as fever when split-virus vaccine is compared to placebo. However, in young children not previously exposed to influenza vaccine, fever, malaise, and myalgia can occur after vaccination. Because inactivated influenza vaccines are not live, they cannot cause influenza. The current vaccines are considerably purer than vaccines produced prior to 1968 and cause far fewer adverse events.

In 1976, the federal government sponsored the National Influenza Immunization Program to give A/New Jersey influenza "swine flu" vaccine to almost all adults in the United States as well as children at high risk of serious illness. The program included a nationwide surveillance system to look for possible adverse reactions and found seven cases of Guillain-Barre syndrome (GBS) by December 2, 1976, when over 35 million doses had been administered. An active surveillance system was established, more cases were discovered, and epidemiologic evidence indicated that some GBS cases were related to vaccination. (124) The risk was approximately 1 case per 1,000,000 vaccinees. This strain of influenza vaccine is no longer in use.

Studies since the 1976 swine influenza vaccine are mixed, with some showing no increased risk and one suggesting a slight increase. If influenza vaccine increases the risk of GBS, the risk is quite small, on the order of 1 to 2 cases per million persons vaccinated. Good evidence shows that a number of infectious diseases--particularly Camphylobacter jejuni, Mycoplasma pneumoniae, cytomegalovirus, and Epstein-Barr virus--provoke GBS. Even if GBS were a tree side effect of vaccination in some years, the risk is substantially less than the risk for severe influenza. The decision about whether to vaccinate persons with a history of GBS should be based on two factors: risk for severe complications if they contract influenza and whether GBS was documented to occur following influenza vaccination. It is prudent to not vaccinate persons who are low risk for complications of influenza dis ease and have a documented history of GBS following previous influenza vaccination. (94) Many experts would vaccinate a person with GBS who is a high risk for complications from influenza. (94)

Recommendations

Routine, annual vaccination is recommended for persons aged 50 years and older. In the event of a vaccine shortage, persons with high-risk conditions and the elderly should have priority for vaccination. Starting in the fall of 2002, the ACIP encourages influenza vaccination of all children aged 6 to 23 months when feasible. Further, the demonstrated high risk of influenza-related hospitalizations among children younger than 6 months who cannot be vaccinated because they are too young led the ACIP to encourage vaccination of the household contacts of such children.

PNEUMOCOCCAL POLYSACCHARIDE VACCINE

Disease burden

Each year, Streptococcus pneumoniae causes an estimated 3,000 to 6,000 cases of meningitis, 50,000 cases of bacteremia, and 500,000 cases of pneumonia in the United States. (125,126)

Incidence and prevalence. It accounts for a major proportion of invasive bacterial disease (bacteremia, meningitis, etc.) in all age groups but is especially dangerous for persons aged [greater than or equal to] 65 years, with an attack rate of 50 to 83 cases per 100,000 persons per year. (125,127)

Risk factors. African Americans, Alaskan Natives, and Native Americans are at increased risk, as are those with certain chronic diseases, immunocompromising conditions, or asplenia. (42,125) Cigarette smoking and passive smoke inhalation are also risk factors for pneumococcal infections, but asthma alone is not. (42,125)

Mortality and resistance. In those over age 70, the mortality rate climbs to 55% to 60%. (128) Compounding this danger is an increasing proportion of penicillin resistant pneumococci, up to 35% in some areas. (125,128) These organisms are often resistant to multiple antibiotics. Despite these data, the current immunization rate of 54% for elderly persons remains well below the 60% goal of Healthy People 2000 and the goal of 90% for noninstitutionalized elderly in Healthy People 2010.

Rationale for vaccination

Vaccine. Pneumococcal polysaccharide vaccine (PPV) contains 23 polysaccharide antigens (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17E 18C, 19A, 19F, 20, 22F, 23F, and 33F) that cover 80% to 90% of the serotypes of invasive pneumococci in children older than 2 years of age and adults, and provides broader coverage than the conjugated pneumococcal vaccine (Figure 1). (127,129,130) The duration of immunity fallowing a single close is unknown, but is at least 9 years in immunocompetent individuals. (129)

Vaccine efficacy. In case control studies, PPV has a 56% to 81% efficacy against invasive pneumococcal disease, with better protection against the serotypes included in the vaccine and in immunocompetent persons. (125) The vaccine may be less effective against nonbacteremic pneumococcal pneumonia. (128,131) However, in a meta-analysis of randomized controlled trials of older pneumococcal polysaccharide vaccines, the efficacy was 66% against definitive pneumococcal pneumonia and 83% against definitive pneumococcal pneumonia for vaccine serotypes. (131) PPV is a cost-effective vaccine. (132)

Adverse reactions. Primary vaccination and revaccination with PPV is extremely safe. (133) It has been reported that 11% of revaccinees, compared to 3% of first time vaccinees, developed large 10.2-cm (4-inch) local reactions when a second PPV was given more than 4 years after the first). (134) However, all of these reactions have been self-limited, generally lasting 3 days, and left no residual. Other reactions include pain at the injection site and, rarely, fever or myalgia. (125)

Recommendations

PPV is recommended for all persons aged [greater than or equal to] 65 years and for those with certain high-risk conditions, outlined in "Vaccines for Persons at High Risk Because of Medical Conditions, Occupation, Environment, or Lifestyle, 2003." Opportunities to vaccinate include routine office visits, scheduled administration in community settings, and during hospitalization after patients have stabilized. In fact, one study showed that 60% of persons [greater than or equal to] 65 years who were hospitalized for pneumonia had been discharged from the hospital within 4 years of readmission. (135)

Revaccination at age 65 years or older is indicated once for persons who received PPV prior to age 65 years, when 5 or more years have elapsed since the first dose (Table 5). Antibody levels significantly increase after this second vaccination but to lower levels than with primary vaccination. Antibody levels may not increase after a third PPV.

Vaccine shortages

In the recent past, due to manufacturing problems, quality improvement projects, or manufacturer withdrawal from vaccine production, shortages of conjugated pneumococcal, tetanus, influenza and varicella vaccines have occurred. For advice on how to best manage potential future shortages, the practitioner should consult the CDC's National Immunization Information Hotline at 1-800-232-2522, or online at the CDC's National Immunization Program at www.cdc.gov.nip.
SPECIAL TOPIC

New vaccines

Development of new vaccines against a
number of diseases is progressing well.
Vaccines that may be available later this
decade include meningococcal conjugate
vaccine, live attenuated influenza vaccine,
acellular pertussis vaccine for adults, human
papillomavirus vaccine, herpes zoster vaccine,
and, for dialysis patients,
Staphylococcus aureus vaccine.

TABLE 1
CASES OF VACCINE-PREVENTABLE DISEASES OF CHILDREN
PRIOR TO ROUTINE USE OF VACCINES

Vaccine-preventable disease   Year *   Annual cases

Hepatitis B                    1989       132,000
Haemophilus influenzae
    type b
  Invasive disease             1986        13,014
  Meningitis                                8,676
Poliomyelitis
  All types                    1954        56,784
  Paralytic                                18,308
Measles                        1964       458,083
Rubella                        1970        57,686

Vaccine-preventable disease        Deaths            Cases in 2000

Hepatitis B                   5,820 ([dagger])            8,036
Haemophilus influenzae
    type b
  Invasive disease              531                   55 ([section])
  Meningitis                    354
Poliomyelitis                                               0
  All types                      --
  Paralytic                      --
Measles                         380                        86
Rubella                          --              185 ([double dagger])

TABLE 2
EFFICACY OF ACELLULAR PERTUSSIS VACCINES: STUDIES OF ADMINISTRATION IN
INFANCY *

             Acellular
Site of      pertussis   Vaccine composition
study        vaccine     PT   FHA   Pn   Fim

Italy        Infanrix    X     X    X
             (SKB-3P)

Germany      Infanrix    X     X    X
             (SKB-3P)

Stockholm,   DAPTACEL    X     X    X     X
Sweden       (CLL-4F2)

Munich,      Tripedia    X     X    X
Germany      (CB-2)

                                                Schedule
Site of                                         studied
study        Trial type                         (months)

Italy        Randomized double-blind             2,4,6

Germany      Household contact with passive      3,4,5
             surveillance

Stockholm,   Randomized double-blind             2,4,6
Sweden

Munich,      Case-control study with passive     3,5,7
Germany      surveillance

                       Vaccine efficacy against
             [greater than or equal to] 21 days of cough

Site of                 DTaP, %               DTP **, %
study                  (95% CI)               (95% CI)

Italy        84 (70-90) ([dagger])           36 (14-52)

Germany      89 (77-95) ([dagger])           98 (83-100)

Stockholm,   85 (81-89)                      48 (37-58)
Sweden

Munich,      80 (59-90) ([double dagger])    95 (81-99)
Germany

Modified from CDC. Pertussis vaccination: use of cellular pertussis
vaccines among infants and young children. Recommendations of the
ACIP. MMWR Recomm Rep 1997;46(RR-7):6.

* PT = pertussis toxin; FHA = filamentous hemagglutinin;
Pn = pertactin; Fim = fimbriae; DTaP = pediatric dose of diphtheria
toxoid and tetanus toxoid and a cellular pertussis vaccine;
DTP = pediatric dose of diphtheria toxoid and tetanus toxoid and
whole-cell pertussis vaccine.

** The whole-cell vaccines differed; some are not available in the
United States.

([dagger]) Efficacy against [greater than or equal to] 21 days of
paroxysmal cough with culture or serologic confirmation.

([double dagger]) Efficacy against [greater than or equal to] 21
days of any cough and confirmation by culture or link to culture;
household contact.

TABLE 3
PERCENTAGE OF INFANTS WITH MILD OR LOCAL REACTIONS BY THIRD EVENING
POST-PERTUSSIS VACCINATION AT AGES 2, 4, AND 6 MOS *

                                           Temperature         Swelling
Vaccine                              [greater than or equal     >20 mm
                                       to] 37.8[degrees]C

Aventis/Biken/CB-2/Tripedia                   24.5                3.7
Aventis/CLL-4[F.sub.2]/DAPTACEL               32.8                4.4
SmithKline Beecham/SKB-3P/Infanrix            31.6                5.8
Overall for 13 DTaP vaccines                  24.5                4.2
DTP vaccines overall                          60.4               22.4

                                            Severe
Vaccine                              fussiness ([dagger])

Aventis/Biken/CB-2/Tripedia                   3.7
Aventis/CLL-4[F.sub.2]/DAPTACEL               3.6
SmithKline Beecham/SKB-3P/Infanrix            5.0
Overall for 13 DTaP vaccines                  4.7
DTP vaccines overall                         12.4

Adapted from data in Decker MD, Edwards KM, Steinhoff MC, et al.
Comparison of 13 acellular pertussis vaccines: adverse reactions.
Pediatrics 1995;96(suppl):557-566.

* DTaP = pediatric dose of diphtheria toxoid and tetanus toxoid and
acellular pertussis vaccine; DTP = pediatric dose of diphtheria toxoid
and tetanus toxoid and whole-cell pertussis vaccine.

([dagger]) Fussiness was classified as severe when the infant cried
persistently and could not be comforted.

TABLE 4
RATES (CASES PER 100,000 POPULATION) OF INVASIVE PNEUMOCOCCAL DISEASE
IN UNITED STATES CHILDHOOD POPULATIONS *

                                               Children with     HIV-
                          African    Alaska     sickle-cell    infected
Age group    All races   Americans   Natives     diseases      children
                                                 ([dagger])

0-5 mos          73         163        277         6,380        4,500
6-11 mos        228         542        598         6,380
12-23 mos       184         441        453         6,340         5,500
24-35 mos        65         116        125         5,720         9,900
36-47 mos        27          46         56           900         5,100
48-59 mos        14          21         73         1,450         2,500
5-9 yrs           6           9
10-19 yrs         3           5

Adapted from Preventing Pneumococcal Disease Among Infants and Young
Children, Recommendations of the Advisory Committee on Immunization
Practices. MMWR Recomm Rep 2000;49(RR-9):5. Public domain.

* Active Bacterial Core Surveillance (ABCs)/Emerging Infections
program (EIP) Network for the US, 2000.

([dagger]) No vaccine or penicillin prophylaxis.

TABLE 5
INDICATIONS FOR REVACCINATION WITH PNEUMOCOCCAL POLYSACCHARIDE
VACCINE (PPV)

                                                  Timing of single
Indication                                        revaccination

Children at increased risk for severe
    pneumococcal infection *
  Ages 2 to 10 years                              Revaccinate in 3
                                                    to 5 years
  Ages >10 years                                  [greater than or
                                                    equal to] 5 years
Adults [is greater than or equal to] 65
  years and received
  first dose prior to age 65                      [greater than or
                                                    equal to] 5 years
Bone marrow transplant patients (BMT)             12 months and 24
                                                    months following
                                                    BMT
Chemotherapy and radiation therapy patients       3 months after
                                                    discontinuation
                                                    of therapy

* Risk factors for severe pneumococcal infection:

1. Functional or anatomic asplenia

2. Conditions associated with rapidly decreasing antibody levels,
especially renal failure or transplantation and nephrotic
syndromes

3. HIV infection

4. Immunosuppression, including malignant neoplasm, especially
leukemia, Hodgkin's disease, and lymphoma

5. Sickle cell disease

6. Children with chronic diseases: cadiovascular, pulmonary
(not asthma), diabetes mellitus, alcoholism, cirrhosis, or
cerebrospinal fluids leaks.

FIGURE 1
SEROTYPE COVERAGE OF INVASIVE PNEUMOCOCCAL DISEASE BY VACCINE TYPE
AND AGE GROUP, UNITED STATES, 1998

Age group in years   % of invasive disease

                          PCV7   PPV23

       <1                  77     91
       1                   80     91
       2                   84     91
       3                   79     91
       4                   67     91
       5-17                52     95
       18-34               62     91
       35-49               50     84
       50-64               52     87
       65-79               53     87
       80+                 60     84

PCV = pneumococcal conjugate vaccine

PPV = pneumococcal polysaccharide vaccine

Note: Table made from bar graph.


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RICHARD KENT ZIMMERMAN, MD, MPH; DONALD B. MIDDLETON, MD; ILENE TIMKO BURNS, MD, MPH; AND RICHARD D. CLOVER, MD

Pittsburgh, Pennsylvania, and Louisville, Kentucky

From the Department of Family Medicine and Clinical Epidemiology, University of Pittsburgh School of Medicine (RKZ, DBM, ITB), the Department of Behavioral and Community Health Sciences, Graduate School of Public Health (RKZ), and Department of Public Health/Health Information Sciences, University of Louisville School of Medicine (RDC). Address correspondence to Richard Kent Zimmerman, MD, MPH; Department of Family Medicine; University of Pittsburgh School of Medicine; 3518 Fifth Ave; Pittsburgh, PA 15261: Phone: (412) 383-2354; Fax (412) 383-2245; E-mail: zimmer@pitt.edu.
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Author:Zimmerman, Richard Kent; Middleton, Donald B.; Burns, Ilene Timko; Clover, Richard D.
Publication:Journal of Family Practice
Geographic Code:1USA
Date:Jan 1, 2003
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