Volume 345:1177-1183

October 18, 2001

Number 16

The Prevention of Pneumococcal Disease in Children

G. Scott Giebink, M.D.

Otitis media in children leads to more than 20 million visits to physicians annually in the United States.^1,2,3 By three years of age, 80 percent of all children in the United States have had at least one episode of otitis media, and 50 percent have had at least three episodes.² Recurrent acute otitis media has its onset almost exclusively before a child's second birthday.² Streptococcus pneumoniae (pneumococcus) is the most common cause of acute otitis media, accounting for approximately 50 percent of all cases.^4,5,6

In addition to being a cause of otitis media, S. pneumoniae remains a major cause of childhood illness and death. At least 1 million children die of pneumococcal infections (pneumonia, meningitis, and bacteremia) each year, mostly in developing countries.⁷ A meta-analysis of the outcomes of bacterial meningitis in developed countries revealed that pneumococcal disease was associated with higher rates of death (15 percent) and neurologic sequelae (12 to 28 percent) than either Haemophilus influenzae or Neisseria meningitidis infection.⁸ Studies in Finland⁹ and France¹⁰ suggest that 13 to 38 percent of community-acquired pneumonia in children is caused by pneumococcus, a finding consistent with the results of a controlled efficacy trial of pneumococcal conjugate vaccine.¹¹ Hence, pneumococcal pneumonia also represents a major disease burden in children.

In February 2000, the Food and Drug Administration (FDA) licensed a 7-valent pneumococcal conjugate vaccine (pneumococcal–CRM197, Wyeth Lederle Vaccines, Pearl River, N.Y.), which is recommended for routine use in infants. This vaccine, together with the identification of risk factors for otitis media and pneumococcal colonization of the nasopharynx, provides new opportunities for preventing and managing pneumococcal disease. Given the increasing prevalence of pneumococci with resistance to multiple antimicrobial drugs, these new approaches should find immediate use.

Pneumococcal Antibiotic Resistance

The overuse of antibiotics has contributed to the rapidly increasing prevalence of drug-resistant S. pneumoniae, making it more complicated to treat pneumococcal disease in young children successfully (Figure 1). Antibiotics are prescribed empirically to virtually all children in the United States who have acute otitis media. Yet 70 percent of severe cases and 90 percent of mild cases of acute otitis media resolve spontaneously with placebo treatment.¹⁴ Moreover, 10 to 30 percent of samples of middle-ear fluid from patients with acute otitis media do not contain viable bacteria. Unfortunately, it is difficult and time-consuming to sample middle-ear fluid by tympanocentesis for culture, a practice that would eliminate empiricism from the selection and use of antibiotics.

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Figure 1. Prevalence of Penicillin-Resistant and Multidrug-Resistant Streptococcus pneumoniae. The data shown on the left are from a 1997 nationwide surveillance study of pneumococci in which 113 isolates were obtained from blood (60 percent from children 2 years of age or younger), 415 isolates from the nasopharynx (76 percent from children 10 years of age or younger), and 440 isolates from the middle ear (66 percent from children 2 years of age or younger).^12 The data shown on the right, illustrating the percentage of pneumococcal isolates that were resistant to more than two classes of antibiotics, were obtained in 1998 from eight U.S. metropolitan regions or states with a total population of 16.5 million under surveillance.^13 Of the 3474 isolates obtained in the 1998 series, 26 percent were from children younger than five years of age.

Among invasive isolates of pneumococcus collected from patients of all ages in sentinel hospitals throughout the United States during 1991 and 1992, 6.6 percent were resistant to penicillin and 5.9 percent had multidrug resistance.¹⁵ By 1993 to 1994, 18.4 percent of the isolates collected from children younger than six years old nationwide were resistant to penicillin, and 13.1 percent were resistant to multiple antibiotics.¹⁶ In a 1997 study of 290 isolates collected from the middle ear of children two years old or younger with acute otitis media throughout the United States, the prevalence of strains that were highly resistant to penicillin (49.7 percent) was higher than that of strains with an intermediate level of resistance to penicillin (19.5 percent).¹² The emergence of cross-resistance among antibiotics extends to trimethoprim–sulfamethoxazole, macrolides, cephalosporins, and clindamycin, and the prevalence of multidrug resistance continues to increase.¹³

Risk Factors for Otitis Media and Nasopharyngeal Carriage

Risk factors have been identified that predispose children to otitis media and drug-resistant S. pneumoniae disease. Male sex, attendance at a child-care center outside the home, the absence of breast-feeding, passive exposure to tobacco smoke, and having a sibling with a history of recurrent otitis media all correlate with an increased risk of otitis media in young children.^2,17 As with many childhood infectious diseases, attendance at a child-care center outside the home greatly increases the risk of otitis media, any pneumococcal infection, and infection with drug-resistant S. pneumoniae.^18,19 Previous antibiotic treatment and an age of less than two years are additional risk factors for otitis media caused by drug-resistant S. pneumoniae.^20,21

The nasopharyngeal carriage of pneumococcus is highly prevalent among young children and predisposes the carrier, his or her siblings, and others in close contact with the carrier to pneumococcal infection. The rates of nasopharyngeal carriage are 44 percent among all children six years old or younger,²² 60 to 80 percent among children attending child-care centers outside the home,^23,24,25 and more than 70 percent among children younger than three years of age who have acute otitis media.²⁶ Drug-resistant strains of S. pneumoniae are highly prevalent among children colonized with pneumococcus. In several studies, drug-resistant S. pneumoniae accounted for 37 to 53 percent of these pneumococci, and the frequency of resistant strains was highest in children younger than two years of age.^22,23,24 Nasopharyngeal carriage of pneumococci is significantly associated with the development of acute otitis media, and children colonized with resistant strains are more likely than others to have unresolved acute otitis media.²²

Treatment of Acute Otitis Media

The widespread prescription of broad-spectrum antibiotics for acute otitis media regardless of the pathogens involved contributes substantially to the current trend toward increasing resistance to antimicrobial drugs, as does the frequent use of antibiotics for nonbacterial pharyngitis and bronchitis. Clinicians should educate parents regarding the appropriate use of antibiotics and strategies to reduce the likelihood of acute otitis media, including breast-feeding for at least three months and eliminating children's exposure to tobacco smoke. The judicious use of antibiotics requires an approach of watchful waiting in cases in which the child is asymptomatic or has red tympanic membrane but no middle-ear effusion.²⁷ The use of tympanocentesis for the culture of middle-ear fluid in patients with acute otitis media that is unresponsive to antibiotic treatment would go far toward the more accurate determination of the appropriate choice of antibiotic therapy.²⁸

The antimicrobial drugs selected for children in whom first-line treatment of acute otitis media with amoxicillin has failed must meet two criteria — effectiveness against beta-lactamase–producing H. influenzae and Moraxella catarrhalis and effectiveness against drug-resistant S. pneumoniae.⁵ The latter requirement is the more restrictive, since recent data on the eradication of drug-resistant S. pneumoniae from the middle ear are lacking for most antibiotics. High-dose amoxicillin (80 to 90 mg per kilogram of body weight per day) plus clavulanate, cefuroxime axetil, and intramuscular ceftriaxone meet these requirements in most cases, and clindamycin is often effective when drug-resistant S. pneumoniae has been proved by tympanocentesis to be the infecting organism.⁵

Vaccination to Prevent Pneumococcal Acute Otitis Media

Clinicians have fewer treatment options today for pneumococcal acute otitis media, given the increasing resistance to antibiotics, the widespread nasopharyngeal carriage among young children, and the associated risk of chronic otitis media. Age, family history, and sex are not modifiable risk factors, and attendance at a child-care center outside the home is a necessity for many families. However, more can be done to prevent otitis media.

Pneumococcal capsular polysaccharide is the principal virulence factor protecting pneumococci against the defense mechanisms of the host. Capsular polysaccharide is a T-cell–independent antigen and, consequently, does not elicit antibody responses in young infants, who lack the mature B lymphocytes necessary for T-cell–independent antibody-mediated immunity. For a vaccine to be effective in infants, it must stimulate a T-cell–dependent antibody response, which is present soon after birth. The 23-valent pneumococcal polysaccharide vaccines that have been available since 1977 elicit a T-cell–independent response and thus do not protect young children, nor do they reduce the nasopharyngeal carriage of pneumococcus.

The conjugation of capsular polysaccharides to proteins alters the properties of the antigen complex and converts the antibody response from T-cell–independent to T-cell–dependent. The experience with H. influenzae type b conjugate vaccines shows how effective this type of vaccine can be in young children. Several pneumococcal conjugate vaccines are in development, and they vary with respect to the serotypes they contain, the carrier proteins they use, and their conjugation chemistry.²⁹ One such conjugate vaccine, the pneumococcal–CRM197 conjugate vaccine, has been approved by the FDA for routine use in infants and toddlers to prevent invasive pneumococcal disease. This conjugate vaccine is a mixture of six purified pneumococcal capsular polysaccharides and one capsular oligosaccharide, each coupled to a nontoxic variant of diphtheria toxin (CRM197). Although no vaccine has been developed to cover all 90 known pneumococcal serotypes, the 7 serotypes included in this vaccine — 4, 6B, 9V, 14, 18C, 19F, and 23F — are those that cause 80 percent of invasive pneumococcal disease in children and approximately 60 percent of pneumococcal acute otitis media.^30,31 These serotypes are also the most resistant to antibiotic therapy,^30,31,32 although resistance is emerging among serotypes not covered by the vaccine.¹³ Other pneumococcal conjugate vaccines that are in development include more serotypes and use different carrier proteins for conjugation and different conjugation chemistry. For example, a 9-valent pneumococcal conjugate vaccine currently under study in Israel and Gambia contains serotypes 1 and 5 in addition to those contained in the pneumococcal–CRM197 conjugate vaccine.

When it is given according to a four-dose schedule of administration at 2, 4, 6, and 12 to 15 months of age, the pneumococcal–CRM197 conjugate vaccine is more than 97 percent effective in preventing invasive pneumococcal disease in healthy infants who have received some or all of these doses of vaccine.¹¹ Unlike the 23-valent pneumococcal polysaccharide vaccines, the pneumococcal–CRM197 conjugate vaccine can induce immunity in the population that is at highest risk for disease. Recently, the Advisory Committee on Immunization Practices and the American Academy of Pediatrics issued recommendations advocating the routine administration of this vaccine to all children 23 months of age or younger and to children between 24 and 59 months of age who are at high risk for pneumococcal infection (i.e., those with conditions causing immunocompromise and certain underlying medical conditions).^33,34 The recommendations also indicate that, when possible, clinicians should consider vaccinating all other children 24 to 59 months of age, with priority given to those who are at moderate risk for pneumococcal infection, including Alaskan Native and American Indian children, those of African-American descent, and children attending child-care centers outside the home.³³

In addition to their immunogenicity and efficacy in preventing invasive disease, pneumococcal conjugate vaccines have been shown to reduce nasopharyngeal carriage of pneumococci^35,36,37 and to reduce the frequency of acute otitis media.^11,38,39 In a randomized, double-blind clinical trial conducted at 23 Northern California Kaiser Permanente medical centers enrolling more than 37,000 children,¹¹ the efficacy of the pneumococcal–CRM197 conjugate vaccine in preventing otitis media was assessed as a secondary outcome. Vaccination reduced the number of episodes of acute otitis media by 7.0 percent and the number of visits to physicians' offices for otitis media by 8.9 percent. The efficacy rate was higher — 22.8 percent — when it was measured in terms of the prevention of frequent otitis media, defined as the occurrence of five episodes of acute otitis media during a six-month period or six episodes during the course of one year (Table 1). Children who received the vaccine were 20.1 percent less likely than controls to require tympanostomy tubes for recurrent acute otitis media or chronic otitis media with effusion. These results are consistent with a study that demonstrated significantly higher concentrations of anticapsular antibody in otitis-prone children after the administration of the pneumococcal–CRM197 conjugate vaccine than after the administration of a 23-valent pneumococcal polysaccharide vaccine.⁴⁰

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Table 1. Summary Results from Three Randomized Clinical Trials Comparing the Efficacy of Two Pneumococcal Polysaccharide–Protein Conjugate Vaccines (Pneumococcal–CRM197 and Pneumococcal–OMPC) in Preventing Otitis Media, Pneumococcal Otitis Media, and Vaccine-Serotype–Specific Pneumococcal Otitis Media.

The ability of pneumococcal conjugate vaccines to protect children against acute otitis media was more thoroughly evaluated in the Finnish Otitis Media Study.^38,39 A total of 2497 children were randomly assigned to receive either the pneumococcal–CRM197 conjugate vaccine, another 7-valent pneumococcal conjugate vaccine (pneumococcal polysaccharides conjugated to meningococcal outer membrane protein complex [OMPC]), or a control (hepatitis B) vaccine at 2, 4, 6, and 12 months of age. Children were followed to 24 months of age. In the comparison between the pneumococcal–CRM197 group and the control group, 2596 episodes of acute otitis media were diagnosed. The overall incidence of acute otitis media was 1.16 episodes per person-year in the pneumococcal–CRM197 vaccine group and 1.24 episodes per person-year in the control group. Samples of middle-ear fluid were obtained for culture from children during 93 percent of all episodes of acute otitis media; 271 episodes of culture-confirmed pneumococcal acute otitis media occurred in the pneumococcal-vaccine group, and 414 episodes occurred in the control group — a 34 percent reduction in the incidence of pneumococcal acute otitis media as a result of vaccination. The efficacy rates were 57 percent against episodes due to the serotypes contained in the vaccine and 51 percent against cross-reactive serotypes (6A, 9N, 18B, 19A, and 23A).

In the comparison between the pneumococcal–OMPC vaccine group and the control group in the Finnish Otitis Media Study, there were 110 episodes of acute otitis media attributed to the serotypes contained in the vaccine in the pneumococcal–OMPC vaccine group and 250 such episodes in the control group — a reduction of 56 percent (95 percent confidence interval, 44 to 66 percent) with vaccination.³⁹ The overall incidence of acute otitis media did not differ between the groups. For the booster dose at 12 months, the last 187 children in the pneumococcal–OMPC conjugate-vaccine group received the 23-valent pneumococcal polysaccharide vaccine, and the others in that group received pneumococcal–OMPC vaccine. Vaccine efficacy after the booster dose was nearly identical in these two subgroups (62 percent and 61 percent, respectively), suggesting that the pneumococcal–OMPC conjugate vaccine effectively primes the child's system for a booster dose of either conjugate or polysaccharide. These results are interesting in the light of the fact that, when given to infants at 2, 4, 6, and 15 months of age, the pneumococcal–OMPC vaccine apparently has lower immunogenicity⁴¹ than the pneumococcal–CRM197 conjugate vaccine.⁴²

A recent analysis of 500 isolates obtained from the middle-ear fluid of patients with pneumococcal acute otitis media (90 percent of whom were children) found that 67 percent of all isolates were covered by the 7-valent pneumococcal conjugate vaccines, and 67 percent and 77 percent, respectively, would be covered by 9-valent and 11-valent pneumococcal conjugate vaccines that are now in development.⁴³ Moreover, 97 percent of antibiotic-resistant strains were covered by each of the vaccine formulations, with no significant differences among the three vaccines. The fact that there was a reduction in pneumococcal carriage and in the prevalence of drug-resistant S. pneumoniae involving the serotypes contained in the vaccine suggests that there is potential for herd immunity, in which the spread of the serotypes that are most commonly associated with disease and antibiotic resistance would be reduced.³⁶

Expectations of Vaccines and Future Vaccine Strategies

Although the pneumococcal–CRM197 conjugate vaccine has a small effect on individual children, it is likely to have a large effect on the prevalence of pneumococcal disease at the population level; it is also likely to cause a considerable reduction in the absolute number of episodes of otitis media, since otitis media is such a common disease.⁴⁴ It has been projected that vaccination with pneumococcal–CRM197 conjugate could prevent more than 12,000 cases of meningitis and bacteremia, 53,000 cases of pneumonia, 116 pneumococcal-related deaths, and 1 million episodes of otitis media per vaccinated birth cohort in the United States.³² It has also been estimated that the effect on otitis media would account for 60 percent of the cost savings expected from the prevention of pneumococcal disease through a vaccination program.³²

One problem is that pediatricians and parents expect that universally administered vaccines will virtually eradicate the disease they target. Clearly, the pneumococcal–CRM197 conjugate vaccine is highly effective in reducing the prevalence of invasive pneumococcal disease. However, its rates of efficacy against acute otitis media are substantially lower than the efficacy rates of vaccines for other vaccine-preventable diseases. Thus, the expectations of physicians and parents regarding the vaccine are not likely to be met solely on the basis of the prevention of otitis media.

The current strategy for the use of the pneumococcal–CRM197 conjugate vaccine relies on vaccination to eliminate most disease-causing pneumococci, including those that are most resistant to antibiotic therapy. Two possible future scenarios could delay progress. The serotypes contained in the vaccine are capable of capsular transformation into other serotypes that can cause disease. Serotype 14 variants of the Spanish clone of serotype 9V and serotype 19F variants of the multidrug-resistant Spanish clone of serotype 23F have arisen through large recombinational replacements of the genetic locus responsible for biosynthesis of the capsule.^45,46 The pneumococcal–CRM197 conjugate vaccine is recommended for routine use in infants and toddlers — persons in whom pneumococcal carriage is significantly more common than it is in adults, which might increase the likelihood of capsular transformation.

The vaccine covers only 7 of the 90 known disease-causing serotypes of pneumococcus, and its widespread use might therefore allow some of the 83 other serotypes to become predominant pathogens. In the Finnish Otitis Media Study, there was a 33 percent increase among the children vaccinated with the pneumococcal–CRM197 conjugate in the incidence of pneumococcal otitis media caused by serotypes not included in the vaccine.³⁸ Although the use of the 23-valent vaccine has not been associated with an apparent increase in disease caused by serotypes not included in that vaccine, it has been used primarily in adults, who have substantially lower rates of pneumococcal carriage.

In the future, pneumococcal-protein vaccines should offer an alternative approach to the prevention of pneumococcal disease and the reduction of carriage. Several proteins that are virulence factors in pneumococcus have been identified. One, pneumococcal surface protein A (PspA), is effective against otitis media in rats, and a mixture of two proteins (PspA and pneumococcal surface adhesion A protein [PsaA]) protects against nasal carriage of pneumococci in mice.⁴⁷ A third protein, pneumolysin, together with PspA, elicits protection against invasive disease. Including these proteins in polysaccharide–protein conjugate vaccines might enhance the vaccines' efficacy against otitis media while providing coverage against serotypes not included in the vaccines.

Viral vaccines provide another approach to the prevention of otitis media, since respiratory virus infection contributes importantly to the pathogenesis of acute otitis media.⁴⁸ At present, influenzavirus vaccine is the only commercially available vaccine for the control of respiratory virus infections. Results of three randomized trials of influenzavirus vaccine indicate that the prevention of viral infection, which usually precedes acute otitis media, is an effective way to prevent the development of acute otitis media. In a Finnish study, the administration of inactivated influenzavirus vaccine led to an incidence of acute otitis media associated with influenza A that was 83 percent lower than that among controls and an overall incidence of acute otitis media that was 36 percent lower than that among controls.⁴⁹ Similar results were found in a study in the United States, in which there were 32 percent fewer episodes of acute otitis media in vaccinated children during the influenza season studied than in controls.⁵⁰ A live attenuated intranasal influenzavirus vaccine was 93 percent effective against culture-confirmed influenza, and vaccinated children had 30 percent fewer episodes of febrile acute otitis media.⁵¹

Respiratory syncytial virus vaccines that are currently being developed do not seem to induce protection against lower-airway disease in young infants and children, and they have not been evaluated in terms of protection against otitis media. However, passively administered antibody against this virus was effective against both respiratory syncytial virus lower-airway disease⁵² and otitis media in a multicenter trial.⁵³ Two attenuated parainfluenza virus vaccines have been found to be safe and immunogenic in infants, but there are insufficient data on their ability to protect against respiratory disease.^54,55

Currently, routine vaccination of all children with the pneumococcal–CRM197 conjugate vaccine is our best strategy for reducing the burden of early-childhood pneumococcal diseases, including otitis media. Continued surveillance of the distribution of pneumococcal serotypes and patterns of drug resistance is necessary and will dictate the development of future vaccine approaches.

Source Information

From the Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis.

Address reprint requests to Dr. Giebink at the Department of Pediatrics, University of Minnesota School of Medicine, MMC-296, 420 Delaware St. S.E., Minneapolis, MN 55455, or at [log in to unmask].

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Edward E. Rylander, M.D.

Diplomat American Board of Family Practice.

Diplomat American Board of Palliative Medicine.