Infections caused by Streptococcus pneumoniae are a leading cause of morbidity and mortality in children worldwide. In the pediatric population, this organism is the most common bacterial cause of otitis media, sinusitis, and bacteremia, and it is one of the most frequent causes of pneumonia and bacterial meningitis, with the highest number of cases occurring during the first 2 years of life.1'2 On an annual basis in the United States, the burden of pneumococcal disease is substantial, with pneumococci accounting for an estimated 7 million cases of otitis media, 500,000 cases of pneumonia, more than 60,000 cases of bacteremia, and 3,000 cases of meningitis, resulting in millions of physician office visits and antibiotic prescriptions.3
Even with the recent availability of the pneumococcal conjugate vaccine in the United States, the ability to prevent pneumococcal infections in young children remains limited. Pneumococcal polysaccharide vaccines have been available for several decades but are not immunogenic in young infants and children, among whom the incidence of disease is greatest.4 Numerous studies have been performed to identify those factors that place young children at increased risk for invasive pneumococcal disease so that other potential strategies for prevention might be developed.5,7
EPIDEMIOLOGY AND NASOPHARYNGEAL CARRIAGE AS A PREREQUISITE FOR DISEASE
More than 90 different pneumococcal serotypes or serogroups have been identified. However, only a small number of the serotypes or serogroups are highly invasive and therefore account for most disease. The serotypes or serogroups that cause most serious infections in the United States are 3, 4, 6B, 9V, 14, 18C, 19F, and 23F, accounting for more than 80% of invasive infections in children younger than 5 years.8,9
Pneumococci are part of the normal pharyngeal flora in healthy children, and all children are colonized from time to time. Carriage of some serotypes may persist for months, especially in young infants. Rates of colonization are influenced by a number of factors, including age, race, and day care attendance, and vary with geographic location and population. Between 25% and 76% of young children are colonized at any point in time, with the highest rates among children who live in institutions or attend day care. Colonization rates decrease with age, dropping to 25% for adolescents and 2% to 9% for adults who are not routinely exposed to young children.10,11
Risk Factors for Invasive Pneumococcal Disease
Nasopharyngeal colonization is a prerequisite for invasive disease. Prospective studies have shown that up to 95% of children in the United States are colonized with at least one pneumococcal serotype before the age of 2 years. In 15% of cases, acquisition of a new pneumococcal strain was associated with either otitis media or invasive disease.10
RISK FACTORS PREDISPOSING TO INVASIVE DISEASE
Infants and children frequently encounter pneumococci in their environment, but whether they develop a pneumococcal infection depends on several risk factors, as shown in the table. These factors may be related to the organism itself, the human host, or the environment.
The degree of invasiveness varies among the more than 90 different pneumococcal serotypes. The invasiveness of a pneumococcal serotype is determined in part by its capsule, structures of its cell wall, and the predominant type of infections caused by the serotype. The serotypes most associated with pediatric infections are among the most invasive and are also most likely to develop antibiotic resistance.12
Studies conducted in the United States showed that children younger than 2 years who attend day care are at higher risk for pneumococcal infection than are those who do not.513 In addition, day care attendance is associated with the spread of drug-resistant S. pneumoniae.14
Underlying medical conditions such as sickle cell disease, asplenia (both congenital and acquired), and immune deficiency place children at increased risk for invasive pneumococcal disease.15 The risk for pneumococcal infection is especially high in children who have decreased immune responsiveness to polysaccharide antigens or reduced serum antibody concentrations as a result of immunosuppressive conditions (eg, congenital humoral immunodeficiency, human immunodeficiency virus infection, or cancer), organ or bone marrow transplantation, immunosuppressive therapy (eg, antineoplastic agents or corticosteroid therapy), or chronic renal failure or nephrotic syndrome.16 Children with sickle cell disease or asplenia (congenital or acquired) are at greatest risk because they are unable to remove encapsulated pneumococci effectively from the bloodstream, and thus are at increased risk of fulminant pneumococcal sepsis, which is associated with high mortality.16
LOCAL PNEUMOCOCCAL DISEASE
Otitis media is one of the most common infectious diseases of childhood and the leading reason for children to be brought to the pediatrician's office. It is estimated that 25% of pediatrician visits are for acute otitis media (AOM) and its sequelae, translating into more than $5 billion in health care costs per year.17 Although it can occur at any age, AOM is a disease that most commonly affects infants and young children, with the peak incidence in the 6- to 18-month age group. By the time children reach their first birthday, 63% have had at least one episode of AOM, and more than 80% have had AOM by the time they are 3 years old.18
As seen in the figure, S. pneumoniae is the most common bacterial cause of AOM, accounting for approximately 50% of cases or an estimated 7 million middle ear infections each year. Other common causes of bacterial otitis media include Haemophilus influenzae (30% of cases), Moraxella catarrhalis (15% of cases), and other miscellaneous bacteria (5% of cases).19
The diagnosis of AOM is based on history and physical findings. In most children, AOM is usually preceded by a viral upper respiratory tract illness with symptoms of nasal congestion, rhinitis, and pharyngitis. Fever (up to 4O0C), malaise, loss of appetite, and earache or ear tugging are common. In young infants, the nonspecific symptoms of fever, refusal to feed, and irritability may be the only symptoms of AOM. The tympanic membrane in AOM is erythematous, dull, and bulging with loss of familiar landmarks.
However, history and clinical symptoms are not predictive of whether AOM is bacterial or nonbacterial and cannot identify the causative organism. Saeed et al, in a study of 73 children between the ages of 3 months and 6 years with AOM, found that nonbacterial and bacterial etiology could not be distinguished by the severity of the child's symptoms. However, they did find that children whose middle ear isolates grew S. pneumoniae were more likely to have a full or bulging tympanic membrane compared with children who had other bacterial pathogens in their middle ear fluid.20 Culture of middle ear fluid is the only way to confirm the cause of AOM, but approximately onethird of cultures are sterile. Of all the bacterial causes of AOM, S. pneumoniae is the least likely to resolve spontaneously and requires therapy for resolution of the infection.
The causative agents in acute sinusitis are much the same as those of AOM, with the major bacterial pathogens being S. pneumoniae (30% to 40% of cases), H. influenzae (20%), and M. catarrhalis (20%).21 As is seen with AOM, sinusitis is a common complication of viral upper respiratory tract infections. Clinical symptoms vary with the age of the child. In young infants, the only symptoms may be fever and irritability. However, persistent rhinorrhea (thin or thick and mucoid, clear, or purulent), with or without cough, malodorous breath, and fever are the most common symptoms reported in all age groups. In older children and adolescents, symptoms may be more localized to the sinuses and include rhinorrhea, headache, facial pain, periorbital edema, and fever (moderate to high grade).22
The diagnosis is usually based on clinical history and physical findings, but cannot be made unless symptoms have been present for more than 10 days without clinical improvement. Radiographic studies (sinus radiographs or computed tomography) or sinus aspiration to obtain material for bacterial culture can confirm the diagnosis.
INVASIVE PNEUMOCOCCAL DISEASE
Invasive pneumococcal disease is defined as infection of normally sterile body sites and is most common in children younger than 5 years.5 Of the invasive forms of disease, meningitis occurs more frequently in children between the ages of 6 and 18 months, whereas bacteremia is most common between the ages of 6 and 36 months. Most cases of pneumococcal pneumonia occur in children between 3 and 60 months of age, whereas most pneumococcal bone and joint infections occur between the ages of 3 and 34 months.23
Meningitis, the most serious invasive pneumococcal disease, typically results from dissemination of the organism to the meninges via the bloodstream and occurs in approximately 1 in 1,000 children younger than 2 years.23 Projections from population-based studies of bacterial meningitis indicate that S. pneumoniae has emerged as the leading cause of bacterial meningitis in the United States since the introduction of the H. influenzae type b conjugate vaccine.24
Patients with pneumococcal meningitis may experience a wide gamut of disease features ranging from a fulminant course that can result in death less than 24 hours after the onset of symptoms to the gradual onset of symptoms that may proceed from nonspecific upper respiratory tract manifestations during several days until the disease becomes obvious. Despite appropriate antibiotic therapy and intensive medical care, a significant level of morbidity continues to be associated with the disease.25
Fever is usually present in children with pneumococcal meningitis but may be absent in young infants. Nonspecific findings of irritability or inconsolability may gradually evolve into decreased activity or lethargy. Refusal to feed increases as the disease progresses and respiratory distress and photophobia may develop later in the disease course. Children old enough to complain report headache early in the course of the disease, and as the meningeal inflammation increases, back pain, stiff neck, and Kernig or Brudzinski signs may be present. As intracranial pressure begins to increase, nausea and vomiting develop. The increase in intracranial pressure may ultimately produce papilledema, confusion, or changes in mental status. Seizures can occur at any time during the disease, but focal seizures or cranial nerve findings suggest central nervous system injury. Eventually, lethargy and shock may ensue. Additional signs and symptoms may develop if other areas become infected as a result of the bacteremic spread of pneumococci.
Early and accurate diagnosis of bacterial meningitis is a major factor in the successful treatment of the infection. Prompt initiation of therapy with intravenous fluids and antibiotics can minimize the severity of the illness, the development of complications, and the emergence of sequelae. If there is suspicion of bacterial meningitis in a child with the appropriate signs and symptoms, lumbar puncture must be performed to obtain cerebrospinal fluid (CSF) for analysis and culture. This is especially important in children younger than 1 year, the age group most susceptible to pneumococcal meningitis.
The typical CSF white blood cell (WBC) count in bacterial meningitis is more than 1,000 cells /mmp 3. However, few or no WBCs may be present in the CSF in the early stages of infection. Most WBCs are polymorphonuclear leukocytes, with the presence of immature polymorphonuclear leukocytes being suggestive of a bacterial infection. In addition, the CSF glucose concentration is usually depressed, whereas the protein concentration is usually elevated. Results of Gram stain of the CSF specimen may be positive in 80% to 90% of patients with untreated meningitis. Detection of polysaccharide antigen in the CSF by latex agglutination may be used to aid in the determination of the etiology of meningitis, especially in patients who have abnormal CSF parameters with a negative result on Gram stain and culture. A positive result on CSF culture is the gold standard in confirming the diagnosis.
The morbidity and mortality associated with pneumococcal meningitis is considerable, even with early diagnosis and appropriate therapeutic intervention. Neurologic sequelae have been detected in 25% to 56% of survivors, and death can be expected in 5% to 15% of cases.25 The most common neurologic sequela is neurosensory hearing loss; however, impairment of motor functions and intellectual processes may occur, and in more severe cases hydrocephaly or neurologic devastation may result.26,27
High rates of pneumococcal bacteremia have been reported in very young children.28 In the United States, the annual incidence of pneumococcal bacteremia in children 4 years or younger is estimated to be 242 cases per 100,000, with approximately 70% of these cases occurring in infants younger than 12 months.29 The incidence of pneumococcal bacteremia has also been shown to vary geographically, with rates as high as 1,195 per 100,000 in Alaskan children younger than 2 years.13
Bacteremia may occur in association with meningitis, pneumonia, or septic arthritis, or may occur concurrently with localized disease, such as AOM. Approximately 3% to 5% of febrile children between the ages of 3 and 36 months are at risk for asymptomatic or occult bacteremia, 85% to 95% of which is caused by S. pneumoniae.30,31 However, identifying these children is problematic, because symptoms may be nonspecific (eg, decreased activity levels, reduced appetite, or irritability). Because bacteremia is diagnosed on the basis of isolation of S. pneumoniae from blood cultures, diagnosis in these cases is generally made because blood cultures were obtained prior to initiation of antibiotic therapy. Although an increased peripheral WBC count (≥ 15,000/ mmp 3) or absolute neutrophil count (≥ 10,000 /mmp 3) has been associated with the risk of occult pneumococcal bacteremia, they have limited value as predictors of this disease because these signs may be indicative of many types of infection.30'32 In most children, occult pneumococcal bacteremia resolves spontaneously without apparent sequelae. However, there is a possibility that persistent bacteremia may spread to the meninges, pleura, bones, or joints, leading to serious morbidity or even death.30
Bacteremia is associated with up to 40% of all cases of pneumococcal pneumonia.28 The casefatality rate for pneumococcal pneumonia is lower for children than for adults (1% vs more than 20%, respectively).33 The clinical presentation of pneumococcal pneumonia in children (especially infants and younger children) is broad, ranging from mild, nonspecific respiratory symptoms that can be managed on an outpatient basis to severe respiratory distress. In a study conducted in the United States, the most common signs and symptoms on presentation were fever, cough, tachypnea, malaise, and emesis.34 The most common findings on physical examination were hypoxia (as measured by pulse oximetry), decreased breath sounds, and crackles over the affected area. Findings on chest radiograph demonstrated lobar consolidation in more than 50% of cases, with multiple lobe involvement in almost 50% of cases and the presence of pleural fluid in almost 40% of cases. Necrotizing pneumonia, pneumatoceles, and lung abscesses were complications seen in more severe cases.
In infants and toddlers, presenting signs and symptoms may not be specific to the respiratory tract. Children in this age group may present with symptoms suggestive of an intra-abdominal process (eg, vomiting, abdominal pain, and distention), particularly if they have lower lobe pneumonia. Patients with upper lobe pneumonia may present with nuchal rigidity that mimics that of meningitis.
Pleural empyema is a common complication of pneumococcal pneumonia that occurs in up to 14% of patients and can cause considerable morbidity. In addition to treatment with antibiotics, children may require chest tube drainage or open thoracoscopy for treatment of empyema.34
Diagnosis of pneumococcal pneumonia is based on a combination of clinical history, physical examination, radiograph findings, and isolation of the organism from blood cultures, pleural fluid cultures, or both. The use of rapid antigen tests for the detection of pneumococcal capsular polysaccharide in pleural fluid or concentrated urine may aid in making the diagnosis.35
Pneumococcal Bone and Joint Infections
Most bone and joint infections in normal children are of hematogenous origin, with trauma preceding infection in up to 36% of cases.36 S. pneumoniae has been identified as the cause of up to 4% of all bacterial bone infections and up to 20% of all bacterial joint infections in children. Bone and joint infections represent approximately 3% of all invasive pneumococcal disease.37,38 The femur and the humerus are the bones most commonly affected; joints most commonly involved include the knees and the hips, and in some cases the vertebrae may be affected.38 Up to 50% of children have arthritis associated with osteomyelitis, and nearly half of all children with bone and joint infections are also bacteremic.38
Often, the earliest signs of bone and joint infections are subtle. Infants often present with irritability and decreased movement of the affected limb, whereas many older children will present with fever and localized signs of infection (eg, redness, swelling, tenderness, and warmth). However, a recent study noted that 10% of children with pneumococcal bone and joint infections were hospitalized without localized signs or symptoms of infection.38 These children were subsequently found to be bacteremic, with signs of infection developing 2 to 5 days after admission, indicating that such infections should be considered in febrile children with no specific focus of disease.38
Diagnosis of septic arthritis, osteomyelitis, or both is made based on a combination of history, local signs of bone or joint inflammation, aspiration of pus from the bone or joint, positive results on culture of the bone, joint, or blood, and radiographic (plain film, bone scan, or magnetic resonance imaging) changes consistent with septic arthritis or osteomyelitis. Peripheral WBC count, differential, erythrocyte sedimentation rate, and C-reactive protein concentration are nonspecific indicators of inflammation that may be used to monitor recovery. Confirmation of the diagnosis requires isolation of the organism from blood, joint fluid, or bone aspirate.
Other Pneumococcal Infections
Some less common infections caused by S. pneumoniae include infective endocarditis (accounting for less than 3% of all endocarditis cases), soft tissue infections (eg, periorbital cellulitis, buccal cellulitis, glossitis, erysipelas, and abscess), pericarditis, parotitis, early-onset neonatal septicemia, primary peritonitis, and salpingitis.
Invasive pneumococcal infections remain a leading cause of morbidity and mortality worldwide, especially in the pediatric population. Children younger than 2 years are most susceptible to pneumococcal infections, a problem that is compounded by the large proportion of these children attending day care centers, an environment that favors the transmission of drug-resistant serotypes. The development of drug-resistant pneumococcal serotypes has focused attention on the prevention of disease via vaccination. However, the currently available 23-valent polysaccharide vaccines are ineffective in children younger than 2 years. The licensed heptavalent pneumococcal conjugate vaccine and other multivalent pneumococcal conjugate vaccines in development have the potential to prevent disease, decrease antibiotic use, and reduce the antibiotic resistance seen with these infections. The extent of this potential remains to be seen. However, these vaccines should provide physicians with an effective means of preventing invasive pneumococcal disease and decrease the current burden of disease significantly.
1. Appelbaum PC. Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae. Pediatr Infect Dis J. 1996;15:932-939.
2. Klein JO. The epidemiology of pneumococcal disease in infants and children. Rev Infect Dis. 1981;3:246-253.
3. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance (ABCs) Report, Emerging Infections Program Network Streptococcus pneumoniae, 1998. Atlanta, GA: Centers for Disease Control and Prevention; 1999. Available at www.cdc.gov/ncidod/ dbmd / abcs / spneu98.pdf.
4. Douglas RM, Paton JC, Duncan SJ, et al. Antibody response to pneumococcal vaccination in children younger than five years of age. J Infect Dis. 1983;148:131137.
5. Levine OS, Farley MF, Harrison LH, et al. Risk factors for invasive pneumococcal disease in children: a populationbased case-control study in North America. Pediatrics. 1999;103:1-5.
6. Deeks SL, Palacio R, Ruvinsky R, et al. Risk factors and course of illness among children with invasive penicillinresistant Streptococcus pneumoniae. Pediatrics. 1999;103:409413.
7. Robinson KA, Baughman W, Rothrock G, et al. Epidemiology of invasive Streptococcus pneumoniae infections in the United States, 1995-1998. JAMA. 2001; 285:1729-1735.
8. Hausdorff WP, Bryant J, Paradiso PR, Siber GR. Which pneumococcal serogroups cause the most invasive disease? Implications for conjugate vaccine formulation and use: Part I. Clin Infect Dis. 2000;30:100-121.
9. Hausdorff WP, Bryant J, Kloek C, Paradiso PR, Siber GR. The contributions of specific pneumococcal serogroups to different disease manifestations. Implications for conjugate vaccine formulation and use: Part ?. Clin Infect Dis. 2000;30:122-140.
10. Gray BM, Converse GM DJ, Dillon HC Jr. Epidemiologic studies of Streptococcus pneumoniae in infants: acquisition, carriage, and infection during the first 24 months of life. J Infect Dis. 1980;142:923-933.
11. Ghaffar F, Friedland IR, McCracken GH Jr. Dynamics of nasopharyngeal colonization by Streptococcus pneumoniae. Pediatr Infect Dis J. 1999;18:638-646.
12. Anderson B, Eriksson B, Falsen E, et al. Adhesion of Streptococcus pneumoniae to human pharyngeal epithelial cells in vitro: differences in adhesive capacity among strains isolated from subjects with otitis media, septicemia, or meningitis or from healthy carriers. Inject Immun. 1981,32:311-317.
13. Gessner BD, Ussery XT, Parkinson AJ, Breiman RF. Risk factors for invasive disease caused by Streptococcus pneumoniae among Alaska native children younger than two years of age. Pediatr infect Dis J. 1995;14:123-128.
14. Boken DJ, Chartrand SA, Goering RV, Kruger R, Harrison CJ. Colonization with penicillin-resistant Streptococcus pneumoniae in a child-care center. Pediatr Infect Dis J. 1995;14:879-884.
15. Committee on Infectious Diseases, American Academy of Pediatrics. Pneumococcal infections. In: Pickering LK, ed. 2000 Red Book: Report of the Committee on Infectious Diseases, 25th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2000:452-460.
16. Centers for Disease Control and Prevention. Preventing pneumococcal disease among infants and young children: recommendations of the Advisory Committee on Immunization Practices (ACTP). MMWR. 2000;49(RR09):1-38.
17. Bondy J, Berman S, Glazner J, Lezotte D. Direct expenditures related to otitis media diagnoses: extrapolations from a pediatric Medicaid cohort. Pediatrics. 2000;105:e72. Available at www.pediatrics.org/cgi/content/full/105/ 6/e72.
18. Teele DW, Klein JO, Rosner B. Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study. J Infect Dis. 1989;160:83-94.
19. Bluestone CD, Stephenson JS, Martin LM. Ten-year review of otitis media pathogens. Pediatr Infect Dis J. 1992;11:S7-S11.
20. Saeed K, McCormick D, Lim-Melia E, et al. Acute otitis media: can clinical findings predict bacterial vs. viral etiology? Presented at the 1999 Pediatric Academic Societies Annual Meeting; May 1-4, 1999; San Francisco, CA. Abstract 201.
21. Wald ER. Sinusitis in children. N Engl J Med. 1992;326:319323.
22. Wald ER. Diagnosis and management of sinusitis in children. Adv Pediatr Infect Dis. 1997;12:1-20.
23. Zangwill KM, Vadheim CM, Vannier AM, Hemenway LS, Greenberg DP, Ward JI. Epidemiology of invasive pneumococcal disease in southern California: implications for the design and conduct of a pneumococcal conjugate vaccine efficacy trial. J Infect Dis. 1996;174:752-759.
24. Schuchat A, Robinson K, Wenger JD, et al. Bacterial meningitis in the United States in 1995. N Engl J Med. 1997;337:970-976.
25. Baraff LJ, Lee SI, Schriger DL. Outcomes of bacterial meningitis in children: a meta-analysis. Pediatr Infect Dis J. 1993;12:389-394.
26. Pikis A, Kavaliotis J, Tsikoulas J, Andrianopoulos P, Venzon D, Manios S. Long-term sequelae of pneumocococcal meningitis in children. CKm Pediatr. 1996;35:72-78.
27. Arditi M, Mason EO Jr, Bradley JS, et al. Three-year multicenter surveillance of pneumococcal meningitis in children: clinical characteristics and outcome related to penicillin susceptibility and dexamethasone use. Pediatrics. 1998;102:1087-1097.
28. Jacobs NM, Lerdkachornsuk S, Metzger WI. Pneumococcal bacteremia in infants and children: a ten-year experience at the Cook County Hospital with special reference to the pneumococcal serotypes isolated. Pediatrics. 1979;64:296-300.
29. Mufson MA, Oley G, Hughey D. Pneumococcal disease in a medium-sized community in the United States. JAMA. 1982;248:1486-1489.
30. Baraff LJ, Bass JW, Fleisher GR, et al. Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Ann Emerg Med. 1993;22:1198-1210.
31. Lee GM, Harper MB. Risk of bacteremia for febrile young children in the post-Haemophiius influenzae type b era. Arch Pediatr Adolesc Med. 1998;152:624-628.
32. Kuppermann N, Fleisher GR, Jaffe DM. Predictors of occult pneumococcal bacteremia in young febrile children. Ann Emerg Med. 1998;31:679-687.
33. Malley R, Ambrosino D. Pneumococcal diseases in children: morbidity, mortality, and resistance. University of Chicago Children's Hospital Reports on Current Concepts in the Use of Pediatric Vaccines. 1998;1:1-8.
34. Tan TQ, Mason EO, Barson WJ, et al. Clinical characteristics and outcome of children with pneumonia attributable to penicillin-susceptible and penicillin-nonsusceptible Streptococcus pneumoniae. Pediatrics. 1998;102:1369-1375.
35. Peter G. The child with pneumonia: diagnostic and therapeutic considerations. Pediatr Infect Dis J. 1988,7:453.
36. Nelson JD. Skeletal infections in children. Adv Pediatr Infect Dis. 1991;6:59-78.
37. Kaplan SL, Mason EO Jr, Barson WJ, et al. Three-year multicenter surveillance of systemic pneumococcal infections in children. Pediatrics. 1998;102:538-545.
38. Bradley JS, Kaplan SL, Tan TQ, et al. Pediatric pneumococcal bone and joint infections. Pediatrics. 1998;102:13761382.
Risk Factors for Invasive Pneumococcal Disease