The Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) has released a technical report on the prevention of pneumococcal infections, including the use of pneumococcal conjugate and polysaccharide vaccines and antibiotic prophylaxis. The AAP technical report appears in the August 2000 issue of Pediatrics.

The purpose of the technical report is to update the epidemiology of pneumococcal infections in children, including those in high-risk populations, and to provide new information on the pneumococcal conjugate vaccine, Prevnar, and capsular polysaccharide vaccines. The AAP committee also reviewed the rationale for the use of prophylactic antibiotics in asplenic children and discussed the use of antibiotics to control pneumococcal outbreaks among children in out-of-home care.

Background

Streptococcus pneumoniae is the most common cause of bacteremia, sepsis, meningitis, pneumonia, sinusitis and acute otitis media. The AAP states that children who are at increased risk of pneumococcal infections include those with anatomic or functional asplenia; those undergoing immunosuppressive chemotherapy; children with congenital and acquired immunodeficiency; those with chronic renal disease; and healthy Native American and African American children. Outbreaks of pneumococcal infection have also increased among children attending out-of-home care.

Epidemiology of Pneumococcal Infections

INVASIVE PNEUMOCOCCAL INFECTION

In the United States, S. pneumoniae is the most common cause of invasive bacterial infection in children. Pneumococci are the most common cause of bacteremia in children between two and 36 months of age who have fever without an identifiable source. They account for more than 84 percent of recovered bacterial pathogens. The highest rates of pneumococcal meningitis (estimated to be 10 per 100,000 population) are seen in children younger than 12 months. The rates of invasive pneumococcal infections in healthy and high-risk children are listed in Table 1.

Pneumococcal disease, other than sepsis and meningitis, is also associated with significant morbidity in children. Community-acquired pneumonia in children is often caused by pneumococcal infection, accounting for 13 to 28 percent of bacterial pneumonia in industrialized countries and up to 28 percent in developing countries. S. pneumoniae is also the most common bacterial cause of acute otitis media and sinusitis.

SICKLE CELL DISEASE AND SPLENECTOMY

A high rate of invasive pneumococcal infection in children with sickle cell disease has been shown in several epidemiologic studies in the past 30 years (Table 1). Before penicillin prophylaxis, pneumococcal polysaccharide vaccine and neonatal screening for hemoglobinopathies were used, the rates of invasive pneumococcal disease in children with sickle cell disease exceeded the rates in healthy children by 20- to 100-fold. The highest risk was seen in children younger than five years.

Children with sickle cell hemoglobinopathy and certain other sickle cell hemoglobinopathies (including thalassemias) have lower rates of infection than do children with SS hemoglobinopathy. However, their rates are much higher than those of other children, and deaths caused by fulminant pneumococcal infection have also been reported in these children. In children with congenital or surgical asplenia, the risk of invasive pneumococcal disease has not been defined.

HUMAN IMMUNODEFICIENCY VIRUS INFECTION

Children with human immunodeficiency virus (HIV) infection have high rates of morbidity and mortality associated with high rates of infection caused by encapsulated bacteria (Table 1). In these children, the most common cause of invasive bacterial infection is S. pneumoniae. Children with HIV infection and acquired immunodeficiency syndrome or those with increased levels of immunoglobulin G or immunoglobulin M have the highest risk of invasive pneumococcal disease.

POPULATIONS AT HIGH RISK OF PNEUMOCOCCAL INFECTION

Certain groups of children of Native American descent have moderate risks of pneumococcal infection, compared with other healthy children. Most Native American children who are at high risk of invasive pneumococcal infection are less than two years of age. The degree of risk may vary by factors other than age, including tribal affiliation and residence on or off a reservation site. African American children have rates of invasive pneumococcal infection that are twofold to threefold higher at all ages from birth to 59 months compared with all children in the United States. The rates of pneumococcal infection in these specific populations are listed in Table 1.

CHILDREN IN OUT-OF-HOME CARE

Out-of-home care is defined as being cared for outside of the home for at least four hours per week. The incidence of pneumococcal disease among children in out-of-home care has increased throughout the past decade in the United States and other developed countries. Out-of-home care also increases the risk of respiratory tract infections, otitis media and invasive pneumococcal infection in U.S. children.

Among children in out-of-home care, outbreaks of invasive pneumococcal disease and respiratory tract infections, along with high rates of pneumococcal colonization, have been reported for several pneumococcal serotypes, particularly 14, 23F and 12F. In such outbreaks, pneumococcal infections have included sepsis, meningitis, purulent conjunctivitis, recurrent otitis media and sinusitis.

Nasopharyngeal carriage of S. pneumoniae is common in young children attending out-of-home care. The serogroups most often associated with respiratory tract carriage in these children have been 6, 14, 19 and 23. Transmission of antibiotic-resistant pneumococci has also been documented.

Pneumococcal Vaccines

PURIFIED CAPSULAR POLYSACCHARIDE PNEUMOCOCCAL VACCINES

There are currently two licensed formulations of pneumococcal polysaccharide vaccine available in the United States: Pnu-Immune 23 and Pneumovax. Each vaccine contains 23 purified pneumococcal capsular polysaccharides of S. pneumoniae serotypes. Based on U.S. surveillance of respiratory tract and invasive pneumococcal isolates, these 23 capsular polysaccharide antigens provide potential serospecific protection against at least 75 percent of pneumococcal infections and potential serogroup cross-protection against an additional 14 percent of isolates. Therefore, these vaccines may protect against 85 to 90 percent of invasive and respiratory infections caused by pneumococci in children in the United States.

The 23-valent pneumococcal polysaccharide vaccine has been recommended for children two years and older who are at increased risk for invasive pneumococcal infection. However, many of the polysaccharides in the vaccine are not immunogenic in children younger than two years, and may not be immunogenic for all serotypes until children are five years or older. Despite at least minimal anti-body responses in children two years and older, a reduction of nasopharyngeal carriage of pneumococci has not been shown.

PROTEIN CONJUGATE PNEUMOCOCCAL VACCINES

Several protein conjugate oligosaccharide and polysaccharide pneumococcal vaccines linked with proteins, such as meningococcal outer membrane protein, tetanus toxoid, a mutant nontoxic diphtheria toxin, CRM₁₉₇ and diphtheria toxoids have been evaluated for safety and immunogenicity in infants and children. These polysaccharide conjugate pneumococcal vaccines have shown good immune responses in infants younger than one year, and memory responses have been observed after booster doses.

HEPTAVALENT PNEUMOCOCCAL CRM197 CONJUGATE VACCINE

The heptavalent pneumococcal conjugate vaccine (PCV7), Prevnar, is made up of seven pneumococcal antigens conjugated to 20 μg of CRM₁₉₇ by reductive amination. The recommended primary series of PCV7 vaccine is three doses given at two, four and six months of age with a minimum of six weeks between doses. A fourth (booster) dose is recommended at 12 to 15 months or at least 60 days after the primary series has been completed. The PCV7 provides potential serotype and serogroup cross-protection for 88 percent of the cases of bacteremia, 82 percent of the cases of meningitis and 71 percent of the cases of pneumococcal otitis media episodes in U.S. children younger than six years.

ADVERSE EFFECTS

According to the AAP, the PCV7 vaccine has an acceptable incidence of adverse effects when administered at two, four, six and 12 to 15 months of age with concurrent administration of recommended, age-appropriate vaccines (diphtheria and tetanus toxoids and acellular pertussis [DTaP], Haemophilus influenzae type b conjugate [HbOC], diphtheria and tetanus toxoids and pertussis [DTP]/HbOC, hepatitis B, oral poliovirus [OPV], inactivated poliovirus [IPV], and measles-mumps-rubella [MMR] and varicella vaccine), compared with the administration to children of a control investigational vaccine of meningococcal C polysaccharide conjugated to CRM₁₉₇. Hepatitis A vaccine has not been given concurrently with PCV7.

Data suggest that PCV7 may be among the most reactogenic (e.g., local reactions and incidence of fever) vaccines of those currently available, including the DTaP and Haemophilus conjugate vaccines. Moderate local reactions (such as any erythema 2.4 cm or more and/or tenderness) occurred at the injection site in 4.9 to 6.1 percent of children after all doses, without a statistically significant increase in the number or severity of these reactions with any subsequent dose in the series (Table 2). The fourth dose, which was given with DTaP and MMR, was associated with the fewest local reactions. Infants experienced local reactions at the PCV7 site less often than at the DTP/HbOC site.

The incidence of fever (body temperature 38°C [100.4°F] within 48 hours of vaccination) occurred in more of the children in the PCV7 group than in those who received the meningococcal C conjugate vaccine when given with DTP/HbOC or DTaP (Table 3). The incidence of fever was nearly twofold higher in the children receiving PCV7, compared with the children who received the meningococcal vaccine, despite a high rate of antipyretic use in both groups. Fever occurs most often after the second or third dose of PCV7 when given concurrently with DTP/HbOC.

Among children who were given DTaP, H. influenzae type b vaccine, and OPV or IPV with PCV7, drowsiness occurred in 27.4 to 48.9 percent, fussiness in 37.6 to 39.9 percent and decreased appetite in 12.7 to 17.8 percent. Antipyretics were also used more often in children receiving PCV7 than in those who received meningococcal conjugate vaccines. Of 727 children who received PCV7 without any concurrent vaccines, body temperatures of at least 38°C (100.4°F) were reported in 13.0 percent and temperatures higher than 39°C (102.2°F) were seen in 1.2 percent. According to the package insert from the U.S. Food and Drug Administration, this group of children also experienced irritability (45.8 percent), drowsiness (15.9 percent), restless sleep (21.2 percent), decreased appetite (18.3 percent), vomiting (6.3 percent), diarrhea (12.8 percent), and rash or hives (1.2 percent).

IMMUNOGENICITY

The protective concentrations of pneumococcal antibody against invasive infections have not been determined, according to the AAP. Based on the levels of anticapsular antibody that are protective against H. influenzae type b infection, a surrogate minimal concentration of protective anticapsular antibody might be at least 0.15 μg per mL. Similar levels of specific pneumococcal antibody (0.1 to 1.15 μg per mL) have been associated with lower mortality in rat models of pneumococcal infection.

When given at two, four, six, and 12 to 15 months of age, the PCV7 vaccine induces good antibody response in infants. After three doses, 92 to 100 percent of children had at least 0.15 mg per mL of antibody against all seven of the vaccine serotypes, and 51 to 90 percent of the children reached a level of at least 1.0 μg per mL against the seven vaccine serotypes. Administration of the fourth dose results in a prompt increase in antibody levels to all seven serotypes.

Antibiotic Prophylaxis

Antibiotic prophylaxis is recommended by the AAP for all children with sickle cell disease starting at two months of age or earlier. In clinical practice, this recommendation is often extended to include all children with congenital asplenia or surgical splenectomy. Recommendations for prophylaxis are based on efficacy against invasive pneumococcal infection, which was demonstrated in children with sickle cell disease who were enrolled in a clinical trial of prophylactic penicillin administration. An 84 percent decrease in the incidence of pneumococcal infection was seen in the children receiving antibiotic prophylaxis.

It is not known if prophylactic doses of penicillin reduce nasopharyngeal carriage of pneumococci. Problems with the use of orally administered prophylactic penicillin in children with sickle cell disease have included reports of breakthrough invasive infections and compliance rates of only 66 percent. The AAP reports that several investigators have also found an increased number of children with sickle cell disease who have nasopharyngeal colonization with penicillin-nonsusceptible strains of pneumococci.

Conclusions

The AAP concludes that pneumococcal conjugate vaccines are a significant new contribution to the potential control of pneumococcal disease in young children. Antibiotic prophylaxis helps to protect children with sickle cell disease or splenectomy. While the use of pneumococcal conjugate vaccines may decrease the need for antibiotic prophylaxis in the future, the emergence of antibiotic-resistant strains of pneumococci threatens to jeopardize the efficacy of current antibiotic prophylactic regimens.

The AAP believes that further studies of pneumococcal conjugate vaccines are needed, including studies of the optimal dosage schedules for safety and efficacy for the administration of PCV7 and 23PS vaccine for healthy and high-risk children older than 24 months.