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Streptococcus pneumoniae bacteraemia in children
International Journal of Antimicrobial Agents 30S (2007) S24–S28
Streptococcus pneumoniae bacteraemia in children C. Myers, Alain Gervaix ∗ Department of Pediatrics, University Hospitals of Geneva, Switzerland
Abstract Occult bacteraemia is the most frequent invasive disease caused by Streptococcus pneumoniae in children less than 3 years of age. Despite the relative frequency of this infection, its management is still a challenging task for paediatricians because fever is often the only symptom and a considerable overlap exists in the clinical presentation of children with fever without a focus due to viral illness and children with occult bacteraemia. Management protocols take into account the age of the patient, the clinical score for severity and the results of laboratory tests such as the white blood cell count, the C-reactive protein and the blood procalcitonin level in order to define accurately who will benefit from an antibiotic treatment. Despite appropriate healthcare facilities and access to care the case fatality rate in developed countries is around 9% in children aged less than 1 year. Prevention with the 7-valent conjugate vaccine against S. pneumoniae will decrease morbidity and mortality associated with invasive disease due to these bacteria. However, replacement by non-vaccine serotypes has been noted in countries where the vaccine is widely used and this concern needs to be monitored carefully over the next few years. © 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Streptococcus pneumoniae; Bacteraemia; Conjugate vaccine; Children
1. Introduction At the beginning of the 21st century, Streptococcus pneumoniae infections remain a serious problem in both developed and developing countries. It is a leading cause of mortality in children younger than 2 years of age with an estimated 1.2 million deaths per year, accounting for 9% of all deaths in the developing world [1]. This bacterium causes more deaths than does any other vaccine-preventable organism [2]. S. pneumoniae diseases are not limited to invasive infections, but are also responsible for localised infection with an estimated 7 million episodes of acute otitis media and 500 000 episodes of pneumonia per year in the United States [1]. The only reservoir of S. pneumoniae is the human nasopharynx. From there, this organism can spread to adjacent mucosal tissues and cause infections such as otitis media, sinusitis and pneumonia. In rare instances, S. pneumoniae can invade the mucosa to reach the bloodstream and cause invasive infections such as bacteraemia, meningitis, septic ∗
Corresponding author. Tel.: +41 22 382 4541; fax: +41 22 382 5423. E-mail address: [email protected] (A. Gervaix).
arthritis and osteomyelitis. The nasopharyngeal carriage of S. pneumoniae is higher in young infants and decreases with age. Acquisition may occur during the first days of life and usually peaks towards the second to third year of life [3]. In studies in which infants were followed from birth and nasopharyngeal culture was obtained at regular intervals, almost every infant was found to acquire at least one pneumococcal serotype at some time. Most infants carry two or three different serotypes during the first years of life [4]. Other studies have shown that the prevalence of carriage can range from 38 to 60% in pre-school children, 29–35% in elementaryschool children and 9–25% in high-school students [5]. The prevalence in adults with no children was 6%. However, contact with young carriers increased the carriage rate in adults and reached 29% when children were present in the home. The duration of carriage depends on age and serotype. Carriage usually lasts 3–4 months, but can last as long as 17 months. Duration of carriage tends to decrease with each successive acquisition. Only 15% of new acquisitions in the first 2 years of life are associated with clinical disease elsewhere in the respiratory tract or with invasive disease [3]. The complex factors that mediate progression from nasopharyngeal carriage to clinical disease are only partially understood.
0924-8579/$ – see front matter © 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2007.06.018
C. Myers, A. Gervaix / International Journal of Antimicrobial Agents 30S (2007) S24–S28
Both local immunity at the mucosal surface and systemic immunity are important contributors as well as concomitant viral infection.
2. Streptococcus pneumoniae invasive disease Corresponding to the decrease in invasive disease caused by Haemophilus influenzae type B after the widespread use of conjugate vaccines, there has been an increase in the percentage of invasive diseases caused by S. pneumoniae. The incidence of invasive pneumococcal diseases (IPD) varies in different countries and populations. These infections are detected by blood cultures in most cases, therefore the incidence is directly related to the rate of obtaining blood cultures in febrile young children [6]. In the late 1990s, the incidence in children younger than 5 years of age was fewer than 25 cases per 100 000 population per year in Western Europe, whereas during the same period, 65–75 cases per 100 000 were reported in the United States [6]. In specific at-risk populations such as Alaskan and Australian natives, the incidence of invasive pneumococcal disease is 10–50 times higher [7]. However, an age-dependent pattern exists that is similar in all studied populations: the highest rate is in infants, it then decreases rapidly towards the age of 5 years, and increases in the population aged over 60 years and peaks again in seniors >65 years. The more common clinical syndromes of invasive pneumococcal disease are bacteraemia, pneumonia (with blood or pleural fluid positive for S. pneumoniae) and meningitis. In a retrospective study we performed on 185 consecutive cases of invasive disease caused by S. pneumoniae in children, bacteraemia was present in 50% of cases, 27% and 16% had pneumonia and meningitis, respectively (Fig. 1). Similar results were reported by Kaplan et al. in a 3-year multicentre surveillance study in the US [8]. The burden of disease caused by S. pneumoniae has been significant, representing 83–92% of positive blood cultures taken from young febrile children presenting to emergency departments in the mid1990s, and the overall prevalence of occult bacteraemia was
Fig. 1. Distribution of the site of invasive pneumococcal infection in children in Geneva from 1988 to 2004 (n = 185).
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1.6–1.9% [9]. Despite the relative frequency of pneumococcal bacteraemia, its management is still a challenging task for paediatricians because fever is often the only symptom and therefore a considerable overlap exists in the clinical presentation of children with fever without a focus, due to viral illness and children with occult bacteraemia. Most of these febrile patients have a self-limiting viral infection, but between 3 and 22% present with serious bacterial infection (SBI) including occult bacteraemia [10,11]. In most cases, the organism will be successfully cleared by host defence mechanisms, but occasionally sepsis or a focal infection such as pneumonia, septic arthritis and meningitis, will develop as a result of seeding. The rate of complications is highly dependent on the infecting organism. Prior to the introduction of systematic immunisation against H. influenzae type B, occult bacteraemia occurred in 3–10% of infants aged 2–36 months who were diagnosed with fever without a focus [12]. Blood cultures were positive for S. pneumoniae in approximately 60–85% of cases and H. influenzae group B was responsible for 5–20% of episodes. The risk of developing bacterial meningitis was 7–13% with sustained occult bacteraemia due to H. influenzae group B, but this was much less likely (1–4%) with bacteraemia due to S. pneumoniae [13]. Although antibiotic treatment is necessary for the young child with serious bacterial infection, it is also important to limit treatment to children at greatest risk as treating children with benign illnesses adds to time, discomfort and costs, and contributes to antibiotic resistance. Strategies for the management of febrile infants aged less than 36 months have been debated for decades. A generally accepted approach is to stratify the management of these febrile young children according to their age [14]. At any age children with a toxic appearance, defined by lethargy, signs of poor perfusion or signs of shock must be rapidly investigated and treated with IV antibiotics. For neonates with fever a full sepsis work-up, including lumbar puncture, blood and CSF cultures and parenteral antibiotic therapy, is also recommended because the risk of serious bacterial illness is more than 12%, but most of the time with bacteria other than S. pneumoniae. In infants aged 1–3 months a clinical evaluation, using scores such as the ‘Rochester’ or the ‘Boston’ criteria, associated with laboratory parameters, are necessary to classify these febrile infants into high- or low-risk groups for serious bacterial infections [14,15]. The children who met the following criteria; well appearance, previously healthy, no focus of infection and normal peripheral WBC count (5–15 × 109 /L), normal absolute band count (≤1.5 × 109 /L), ≤10 WBC/high-power field (hpf) on centrifuged urine and ≤5 WBC/hpf on stool smear in patients with diarrhoea, are unlikely to have serious bacterial infection, with a negative predictive value of 98.9%. They can be discharged without antibiotic treatment if follow-up within 24 h can be assured. In the subset of children who do not meet these criteria, antibiotic treatment is recommended pending the results of cultures of blood, urine and CSF. Ceftriaxone, 50 mg/kg IM or IV (100 mg/kg if meningitis is suspected) is
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C. Myers, A. Gervaix / International Journal of Antimicrobial Agents 30S (2007) S24–S28
commonly used for these patients. Finally, in children from 3 to 36 months the first criterion to consider is their temperature. In patients with a fever less than 39 ◦ C, the risk of occult pneumococcal bacteraemia is less than 1% [16], and a careful clinical follow-up is recommended. If fever is ≥39 ◦ C the approach is more selective, but also depends on WBC count, catheterised urine specimen and pneumococcal vaccination status. All these considerations have been recently reviewed by Ishimine [11]. In order to find more sensitive predictors of SBI, recent studies have compared the value of clinical scores, WBC count and inflammatory markers such as C-reactive protein, procalcitonin and IL-6. Our group has shown that procalcitonin at a level ≥0.5 g/L and C-reactive protein ≥40 mg/L had positive and negative likelihood ratios largely superior to WBC count or clinical scores to predict a serious bacterial infection in young children with a fever without source [10,17]. Comparable results were found by other groups [18,19]. However, because the prevalence of SBI is low in young infants with fever without a focus, these clinical and biological markers are more useful to rule out rather than to confirm a SBI. Treatment of invasive pneumococcal infections has become a challenge because of a dramatic increase of penicillin-non-susceptible S. pneumoniae strains [20]. In most cases of penicillin-susceptible and penicillinintermediate S. pneumoniae (MICs ≤1.0 g/mL) most parenteral and some oral antibiotics, such as amoxicillin, achieve serum concentrations that exceed the MIC of the organism for an adequate period. However, in many regions, reports of treatment failure, especially in patients with invasive multidrug-resistant pneumococci, have increased. In critically ill infants and children, amoxicillin has been replaced as first-line treatment by a third-generation cephalosporin (ceftriaxone or cefotaxime), alone or with vancomycin if meningitis is suspected, until susceptibility test results of S. pneumoniae to alternative agents are determined. Among more than 90 immunologically distinct serotypes of pneumococcus, varying in the structure of their polysaccharide capsule, serotypes 6B, 9V, 14, 19F and 23F are responsible for most antibiotic-resistant infections.
3. Prevention of Streptococcus pneumoniae invasive disease Due to the high morbidity and mortality of pneumococcal infections, prevention in all ages is a more effective approach to reduce the burden of disease than any other treatment modality. Until recently the only vaccine available against S. pneumoniae was a 23-valent polysaccharide vaccine. Unfortunately, infants and children less than 2 years of age respond poorly to T-independent antigens and polysaccharide vaccines failed to elicit a protective immune response in this age group, which, as a consequence, bears the burden of 80% of invasive pneumococcal disease.
However, the covalent coupling of weakly immunogenic polysaccharides with a carrier protein, called conjugate vaccine, elicits strong antibody production and booster response when the same antigen is encountered subsequently. Therefore, based on the experience acquired with the widespread use of Haemophilus influenzae type B conjugate vaccine and the major impact on the reduction of invasive disease due to this organism, a conjugate vaccine against S. pneumoniae was developed. Hausdorff et al. reported in an extensive review on pneumococcal serogroups causing the most invasive diseases, that seven serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) were responsible for about 80% (90% if serogroups were considered) of invasive pneumococcal disease in children less than 6 years of age in the USA [21]. This proportion was lower in Western Europe (around 60%) and Asia (around 45%) [21] and among older US children and adults (50–60%). As a consequence, a 7-valent conjugate pneumococcal vaccine (PCV7) was developed and licensed in March 2000 in the United States for routine use in children aged <5 years. Three primary doses of vaccine were recommended at 2, 4 and 6 months of age with a booster dose at 12–15 months. Efficacy study results were impressive with a substantial decrease of 69% of IPD in children 2 years old or less (59.0 cases/100 000 in 2001 compared with 188.0/100 000 in 1988 and 1999) within 21 months of licensure. This decrease was also significant in children 24–35 months old [22]. If the analysis was restricted to the vaccine serotypes, the decline was even greater (78%) for children under 2 years of age. In this population, the changes in the rates of IPD according to serotypes were highly significant (P < 0.001) for all vaccine serotypes but not significant for non-vaccine serotypes, indicating a true effect of the vaccine. Three years after licensure, Black et al. reported in northern California a percent reduction of IPD of 93.7, 90.9 and 84.1% in children <1 year old, <2 years old and <5 years old, respectively and 98.8–100% if restricted to vaccine serotypes [23]. As a consequence, the overall incidence of occult bacteraemia among highly febrile young children in the era of pneumococcal conjugate vaccine has dropped below 1%. Stoll and Rubin reported that, of 329 blood cultures obtained from febrile children 2–36 months of age with fever ≥39 ◦ C, only three were positive for S. pneumoniae (0.91%, 95% CI: 0–1.9%) despite data suggesting a relatively low rate of PCV7 immunization [24]. In one child, the serotype was not included in the vaccine, and a second child had two episodes of bacteraemia 1 month apart. The serotype of this S. pneumoniae was included in the vaccine (serotype 4) but the child was not vaccinated. In contrast to the pneumococcal polysaccharide vaccine, PCV7 was also shown to affect nasopharyngeal carriage and transmission by decreasing the carriage of vaccine serotypes. Therefore by analysing the overall rate of IPD in populations where PCV7 was widely used, several studies have reported a strong herd effect. Indeed, the incidence of IPD decreased not only in vaccinated children but also in older children and in the adult population [22,23]. As of 2003, the total incidence
C. Myers, A. Gervaix / International Journal of Antimicrobial Agents 30S (2007) S24–S28
of IPD in persons aged ≥65 years declined to 41.7 cases per 100 000 vs. 60 cases per 100 000 before the PCV7 era (30.5% decline) [25]. Significant reduction was also noted in people aged 20–39 and 40–64 years old. Because the burden of invasive pneumococcal disease is mainly in the adult population and taking into account the direct and indirect (herd effect) effectiveness of the PCV7, an analysis by the CDC revealed that, of the projected 29 599 cases of IPD due to vaccine type prevented in the USA by PCV7 in 2003 compared with 1998 and 1999, 9140 cases (31%) would be prevented by direct effect in vaccinated children and 20 459 cases (69%) by indirect effect of the vaccine across all ages. In other words, if you vaccinate one child with PCV7 you protect this child and two adults from invasive pneumococcal disease [26]. Another striking effect of PCV7 in the management of occult pneumococcal bacteraemia and other IPDs in children is its impact on antibiotic-resistant strains of S. pneumoniae. Worldwide, most antibiotic-resistant infections are caused by five of the seven serotypes included in PCV7 (6B, 9V, 14, 19F and 23F). In 1998, 24% of invasive pneumococcal isolates in the US were non-susceptible to penicillin, and these five serotypes accounted for 78% of such strains. As a consequence, we could expect that reduction of vaccine type IPD by vaccination should also reduce the percentage of circulating resistant strains of S. pneumoniae. Several recent studies addressing this question proved this to be true [23]. Kyaw et al. measured disease caused by antibioticnon-susceptible S. pneumoniae from 1996 through 2004 [27]. Isolates underwent serotyping and susceptibility testing. Results showed that overall, non-susceptible strains peaked in 1999 and decreased by 57% by 2004. This decline in the percentage of resistant strains occurred in all age groups, 81% in children aged less than 2 years, and 49% among persons 65 years or older. Restricting this analysis to vaccine-type S. pneumoniae the decline of non-susceptible strains was 98% and 79% for these two populations, respectively. However, the possibility that use of a vaccine that targets only seven of the 90 pneumococcal serotypes would lead to an increase in disease by non-vaccine types was addressed in the same study. The authors clearly showed an increase in the incidence of IPD caused by non-vaccine serotypes (so-called replacement strains) [27]. Indeed from 1999 to 2004 this incidence increased from 0.2 cases per 100 000 to 0.5 cases per 100 000 affecting all ages. Serotype 19A was particularly involved. Compared with an overall decline of IPD from 96.7 cases per 100 000 in 1998–1999 to 23.9 cases per 100 000 in 2003 among children aged <5 years, an increase of IPD due to non-vaccine serotypes of 0.2 cases to 0.5 cases per 100 000 does not bring into question the widespread use of this vaccine, but surveillance of this replacement phenomenon needs to be performed. Conjugate vaccines containing 11- and 13serotypes, including the replacement strains that emerged and strains that circulate in Europe and Asia, are under development.
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4. Conclusions S. pneumoniae bacteraemia is still a feared disease in young children because the clinical signs and symptoms are often indistinguishable from a banal viral disease, but if not treated can lead to severe disease such as sepsis or meningitis, which encompass substantial morbidity and mortality. Therefore, the conjugate vaccine that is now available against S. pneumoniae is a major advance in the struggle against this bacterium. Its immunogenicity in children from 2 months of age and its efficiency in decreasing nasopharyngeal carriage of vaccine serotypes have allowed a substantial and rapid decrease in invasive pneumococcal disease, not only in vaccinated children but also in older children and adults. Furthermore, because five serotypes very frequently associated with resistance to multiple antibiotics are included in the vaccine, an overall decrease in the incidence of invasive pneumococcal disease caused by drug-resistant strains has been noted. However, the serotype coverage of invasive S. pneumoniae strains included in the actual 7-valent vaccine is very variable from one country to another; in the range of 80–90% in the United States, but only 18–75% in Western Europe and around 45% in Asia. Moreover, replacement by non-vaccine serotypes has been noted in countries where the vaccine is widely used and this concern needs to be monitored carefully over the next few years. Finally, the global coverage of a population against invasive pneumococcal disease will depend on the vaccine uptake and a full immunisation of infants and children. Efforts should still be made in many countries to reach these objectives and to obtain results comparable to those in the United States. For all these reasons, in most countries the management of febrile children less than 36 months of age should not be modified before local assessment of the real impact of vaccination on the risk of developing a S. pneumoniae bacteraemia. Funding: No funding sources. Competing interests: None declared. Ethical approval: Not required.
References [1] Global Programme for Vaccines and Immunization. Report of the meeting of the Scientific Group of Experts (SAGE) of the Children’s Vaccine Initiative and the Global Programme for Vaccines and Immunization. Geneva, Switzerland: World Health Organization, 1996. [2] Gardner P, Schaffner W. Immunization of adults. N Engl J Med 1993;328:1252–8. [3] Gray BM, Turner ME, Dillon Jr HC. Epidemiologic studies of Streptococcus pneumoniae in infants: The effects of season and age on pneumococcal acquisition and carriage in the first 24 months of life. Am J Epidemiol 1982;116:692–703. [4] Aniansson G, Alm B, Anderson B, et al. Nasopharyngeal colonization during the first year of life. J Infect Dis 1992;165:S38–42. [5] Hendley JO, Sande MA, Stewart PM, Gwaltney JMJ. Spread of Streptococcus pneumoniae in families: Carriage rates and distribution of types. J Infect Dis 1975;132:55–61.
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[6] Hausdorff WP, Siber G, Paradiso PR. Geographical differences in invasive pneumococcal disease rates and serotype frequency in young children. Lancet 2001;357:950–2. [7] Cortese MM, Wolff M, Almeido-Hill J, et al. High incidence rates of invasive pneumococcal disease in the White Mountain Apache population. Arch Intern Med 1992;152:2277–82. [8] Kaplan SL, Mason EO, Barson WJ, et al. Three-year multicenter surveillance of systemic pneumococcal infections in children. Pediatrics 1998;102:538–45. [9] Alpern ER, Alessandrini EA, Bell LM, Shaw KN, McGowan KL. Occult bacteremia from a pediatric emergency department: current prevalence, time to detection, and outcome. Pediatrics 2000;106:505–11. [10] Galetto Lacour A, Gervaix A, Zamora S, et al. Procalcitonin, IL-6, 1L-8, IL-1 receptor antagonist and C-reactive protein dosage as identificators of severe bacterial infections in children with fever without localising signs. Eur J Pediatr 2001;160:95–100. [11] Ishimine P. Fever without source in children 0–36 months of age. Pediatr Clin N Am 2006;53:167–94. [12] Teele DW, Pelton SI, Grant MJ, et al. Bacteremia in febrile children under 2 years of age: results of culture of blood of 600 consecutive febrile children seen in a “walk-in” clinic. J Pediatr 1975;87:227– 30. [13] Shapiro ED, Aaron NH, Wald ER, Chiponis D. Risk factors for development of bacterial meningitis among children with occult bacteremia. J Pediatr 1986;109:15–9. [14] Baraff LJ, Bass JW, Fleischer GR, et al. Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Pediatrics 1993;92:1–12. [15] Slater M, Krug SE. Evaluation of the infant with fever without source: an evidence based approach. Emerg Med Clin North Am 1999;17:97–126. [16] Kuppermann N. Occult bacteremia in young febrile children. Pediatr Clin North Am 1999;46:1073–107. [17] Galetto Lacour A, Zamora SA, Gervaix A. Bedside procalcitonin and C-reactive protein tests in children with fever without localizing
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signs of infection seen in a referral center. Pediatrics 2003;112:1054– 60. Fernandez Lopez A, Luaces Cubells C, Garcia Garcia JJ, Fernandez Pou J. Procalcitonin in pediatric emergency departments for the early diagnosis of invasive bacterial infections in febrile infants: results of a multicenter study and utility of a rapid qualitative test for this marker. Pediatr Infect Dis J 2003;22:895–903. Van Rossum AM, Wulkan RW, Oudesluys-Murphy AM. Procalcitonin as a early marker of infection in neonates and children. Lancet Infect Dis 2004;4:620–30. Jaecklin T, Rohner P, Jacomo V, Schmidheiny K, Gervaix A. Trends in antibiotic resistance of respiratory tract pathogens in children in Geneva, Switzerland. Eur J Pediatr 2006;165:3–8. 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;30:100–21. Withney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003;348:1737–46. Black S, Shinefield H, Baxter R, et al. Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser permanente. Pediatr Infect Dis J 2004;23:485–9. Stoll ML, Rubin LG. Incidence of occult bacteremia among highly febrile young children in the era of the pneumococcal conjugate vaccine. Arch Pediatr Adolesc Med 2004;158:671–5. Lexau CA, Lynfield R, Danila R, et al. Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine. JAMA 2005;294:2043–51. CDC. Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease—United States, 1998–2003. MMWR 2005:54;893-7. Kyaw MH, Lynfield R, Schaffner W, et al. Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae. N Engl J Med 2006;354:1455–63.
Streptococcus pneumoniae bacteraemia in children C. Myers, Alain Gervaix ∗ Department of Pediatrics, University Hospitals of Geneva, Switzerland
Abstract Occult bacteraemia is the most frequent invasive disease caused by Streptococcus pneumoniae in children less than 3 years of age. Despite the relative frequency of this infection, its management is still a challenging task for paediatricians because fever is often the only symptom and a considerable overlap exists in the clinical presentation of children with fever without a focus due to viral illness and children with occult bacteraemia. Management protocols take into account the age of the patient, the clinical score for severity and the results of laboratory tests such as the white blood cell count, the C-reactive protein and the blood procalcitonin level in order to define accurately who will benefit from an antibiotic treatment. Despite appropriate healthcare facilities and access to care the case fatality rate in developed countries is around 9% in children aged less than 1 year. Prevention with the 7-valent conjugate vaccine against S. pneumoniae will decrease morbidity and mortality associated with invasive disease due to these bacteria. However, replacement by non-vaccine serotypes has been noted in countries where the vaccine is widely used and this concern needs to be monitored carefully over the next few years. © 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Streptococcus pneumoniae; Bacteraemia; Conjugate vaccine; Children
1. Introduction At the beginning of the 21st century, Streptococcus pneumoniae infections remain a serious problem in both developed and developing countries. It is a leading cause of mortality in children younger than 2 years of age with an estimated 1.2 million deaths per year, accounting for 9% of all deaths in the developing world [1]. This bacterium causes more deaths than does any other vaccine-preventable organism [2]. S. pneumoniae diseases are not limited to invasive infections, but are also responsible for localised infection with an estimated 7 million episodes of acute otitis media and 500 000 episodes of pneumonia per year in the United States [1]. The only reservoir of S. pneumoniae is the human nasopharynx. From there, this organism can spread to adjacent mucosal tissues and cause infections such as otitis media, sinusitis and pneumonia. In rare instances, S. pneumoniae can invade the mucosa to reach the bloodstream and cause invasive infections such as bacteraemia, meningitis, septic ∗
Corresponding author. Tel.: +41 22 382 4541; fax: +41 22 382 5423. E-mail address: [email protected] (A. Gervaix).
arthritis and osteomyelitis. The nasopharyngeal carriage of S. pneumoniae is higher in young infants and decreases with age. Acquisition may occur during the first days of life and usually peaks towards the second to third year of life [3]. In studies in which infants were followed from birth and nasopharyngeal culture was obtained at regular intervals, almost every infant was found to acquire at least one pneumococcal serotype at some time. Most infants carry two or three different serotypes during the first years of life [4]. Other studies have shown that the prevalence of carriage can range from 38 to 60% in pre-school children, 29–35% in elementaryschool children and 9–25% in high-school students [5]. The prevalence in adults with no children was 6%. However, contact with young carriers increased the carriage rate in adults and reached 29% when children were present in the home. The duration of carriage depends on age and serotype. Carriage usually lasts 3–4 months, but can last as long as 17 months. Duration of carriage tends to decrease with each successive acquisition. Only 15% of new acquisitions in the first 2 years of life are associated with clinical disease elsewhere in the respiratory tract or with invasive disease [3]. The complex factors that mediate progression from nasopharyngeal carriage to clinical disease are only partially understood.
0924-8579/$ – see front matter © 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2007.06.018
C. Myers, A. Gervaix / International Journal of Antimicrobial Agents 30S (2007) S24–S28
Both local immunity at the mucosal surface and systemic immunity are important contributors as well as concomitant viral infection.
2. Streptococcus pneumoniae invasive disease Corresponding to the decrease in invasive disease caused by Haemophilus influenzae type B after the widespread use of conjugate vaccines, there has been an increase in the percentage of invasive diseases caused by S. pneumoniae. The incidence of invasive pneumococcal diseases (IPD) varies in different countries and populations. These infections are detected by blood cultures in most cases, therefore the incidence is directly related to the rate of obtaining blood cultures in febrile young children [6]. In the late 1990s, the incidence in children younger than 5 years of age was fewer than 25 cases per 100 000 population per year in Western Europe, whereas during the same period, 65–75 cases per 100 000 were reported in the United States [6]. In specific at-risk populations such as Alaskan and Australian natives, the incidence of invasive pneumococcal disease is 10–50 times higher [7]. However, an age-dependent pattern exists that is similar in all studied populations: the highest rate is in infants, it then decreases rapidly towards the age of 5 years, and increases in the population aged over 60 years and peaks again in seniors >65 years. The more common clinical syndromes of invasive pneumococcal disease are bacteraemia, pneumonia (with blood or pleural fluid positive for S. pneumoniae) and meningitis. In a retrospective study we performed on 185 consecutive cases of invasive disease caused by S. pneumoniae in children, bacteraemia was present in 50% of cases, 27% and 16% had pneumonia and meningitis, respectively (Fig. 1). Similar results were reported by Kaplan et al. in a 3-year multicentre surveillance study in the US [8]. The burden of disease caused by S. pneumoniae has been significant, representing 83–92% of positive blood cultures taken from young febrile children presenting to emergency departments in the mid1990s, and the overall prevalence of occult bacteraemia was
Fig. 1. Distribution of the site of invasive pneumococcal infection in children in Geneva from 1988 to 2004 (n = 185).
S25
1.6–1.9% [9]. Despite the relative frequency of pneumococcal bacteraemia, its management is still a challenging task for paediatricians because fever is often the only symptom and therefore a considerable overlap exists in the clinical presentation of children with fever without a focus, due to viral illness and children with occult bacteraemia. Most of these febrile patients have a self-limiting viral infection, but between 3 and 22% present with serious bacterial infection (SBI) including occult bacteraemia [10,11]. In most cases, the organism will be successfully cleared by host defence mechanisms, but occasionally sepsis or a focal infection such as pneumonia, septic arthritis and meningitis, will develop as a result of seeding. The rate of complications is highly dependent on the infecting organism. Prior to the introduction of systematic immunisation against H. influenzae type B, occult bacteraemia occurred in 3–10% of infants aged 2–36 months who were diagnosed with fever without a focus [12]. Blood cultures were positive for S. pneumoniae in approximately 60–85% of cases and H. influenzae group B was responsible for 5–20% of episodes. The risk of developing bacterial meningitis was 7–13% with sustained occult bacteraemia due to H. influenzae group B, but this was much less likely (1–4%) with bacteraemia due to S. pneumoniae [13]. Although antibiotic treatment is necessary for the young child with serious bacterial infection, it is also important to limit treatment to children at greatest risk as treating children with benign illnesses adds to time, discomfort and costs, and contributes to antibiotic resistance. Strategies for the management of febrile infants aged less than 36 months have been debated for decades. A generally accepted approach is to stratify the management of these febrile young children according to their age [14]. At any age children with a toxic appearance, defined by lethargy, signs of poor perfusion or signs of shock must be rapidly investigated and treated with IV antibiotics. For neonates with fever a full sepsis work-up, including lumbar puncture, blood and CSF cultures and parenteral antibiotic therapy, is also recommended because the risk of serious bacterial illness is more than 12%, but most of the time with bacteria other than S. pneumoniae. In infants aged 1–3 months a clinical evaluation, using scores such as the ‘Rochester’ or the ‘Boston’ criteria, associated with laboratory parameters, are necessary to classify these febrile infants into high- or low-risk groups for serious bacterial infections [14,15]. The children who met the following criteria; well appearance, previously healthy, no focus of infection and normal peripheral WBC count (5–15 × 109 /L), normal absolute band count (≤1.5 × 109 /L), ≤10 WBC/high-power field (hpf) on centrifuged urine and ≤5 WBC/hpf on stool smear in patients with diarrhoea, are unlikely to have serious bacterial infection, with a negative predictive value of 98.9%. They can be discharged without antibiotic treatment if follow-up within 24 h can be assured. In the subset of children who do not meet these criteria, antibiotic treatment is recommended pending the results of cultures of blood, urine and CSF. Ceftriaxone, 50 mg/kg IM or IV (100 mg/kg if meningitis is suspected) is
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commonly used for these patients. Finally, in children from 3 to 36 months the first criterion to consider is their temperature. In patients with a fever less than 39 ◦ C, the risk of occult pneumococcal bacteraemia is less than 1% [16], and a careful clinical follow-up is recommended. If fever is ≥39 ◦ C the approach is more selective, but also depends on WBC count, catheterised urine specimen and pneumococcal vaccination status. All these considerations have been recently reviewed by Ishimine [11]. In order to find more sensitive predictors of SBI, recent studies have compared the value of clinical scores, WBC count and inflammatory markers such as C-reactive protein, procalcitonin and IL-6. Our group has shown that procalcitonin at a level ≥0.5 g/L and C-reactive protein ≥40 mg/L had positive and negative likelihood ratios largely superior to WBC count or clinical scores to predict a serious bacterial infection in young children with a fever without source [10,17]. Comparable results were found by other groups [18,19]. However, because the prevalence of SBI is low in young infants with fever without a focus, these clinical and biological markers are more useful to rule out rather than to confirm a SBI. Treatment of invasive pneumococcal infections has become a challenge because of a dramatic increase of penicillin-non-susceptible S. pneumoniae strains [20]. In most cases of penicillin-susceptible and penicillinintermediate S. pneumoniae (MICs ≤1.0 g/mL) most parenteral and some oral antibiotics, such as amoxicillin, achieve serum concentrations that exceed the MIC of the organism for an adequate period. However, in many regions, reports of treatment failure, especially in patients with invasive multidrug-resistant pneumococci, have increased. In critically ill infants and children, amoxicillin has been replaced as first-line treatment by a third-generation cephalosporin (ceftriaxone or cefotaxime), alone or with vancomycin if meningitis is suspected, until susceptibility test results of S. pneumoniae to alternative agents are determined. Among more than 90 immunologically distinct serotypes of pneumococcus, varying in the structure of their polysaccharide capsule, serotypes 6B, 9V, 14, 19F and 23F are responsible for most antibiotic-resistant infections.
3. Prevention of Streptococcus pneumoniae invasive disease Due to the high morbidity and mortality of pneumococcal infections, prevention in all ages is a more effective approach to reduce the burden of disease than any other treatment modality. Until recently the only vaccine available against S. pneumoniae was a 23-valent polysaccharide vaccine. Unfortunately, infants and children less than 2 years of age respond poorly to T-independent antigens and polysaccharide vaccines failed to elicit a protective immune response in this age group, which, as a consequence, bears the burden of 80% of invasive pneumococcal disease.
However, the covalent coupling of weakly immunogenic polysaccharides with a carrier protein, called conjugate vaccine, elicits strong antibody production and booster response when the same antigen is encountered subsequently. Therefore, based on the experience acquired with the widespread use of Haemophilus influenzae type B conjugate vaccine and the major impact on the reduction of invasive disease due to this organism, a conjugate vaccine against S. pneumoniae was developed. Hausdorff et al. reported in an extensive review on pneumococcal serogroups causing the most invasive diseases, that seven serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) were responsible for about 80% (90% if serogroups were considered) of invasive pneumococcal disease in children less than 6 years of age in the USA [21]. This proportion was lower in Western Europe (around 60%) and Asia (around 45%) [21] and among older US children and adults (50–60%). As a consequence, a 7-valent conjugate pneumococcal vaccine (PCV7) was developed and licensed in March 2000 in the United States for routine use in children aged <5 years. Three primary doses of vaccine were recommended at 2, 4 and 6 months of age with a booster dose at 12–15 months. Efficacy study results were impressive with a substantial decrease of 69% of IPD in children 2 years old or less (59.0 cases/100 000 in 2001 compared with 188.0/100 000 in 1988 and 1999) within 21 months of licensure. This decrease was also significant in children 24–35 months old [22]. If the analysis was restricted to the vaccine serotypes, the decline was even greater (78%) for children under 2 years of age. In this population, the changes in the rates of IPD according to serotypes were highly significant (P < 0.001) for all vaccine serotypes but not significant for non-vaccine serotypes, indicating a true effect of the vaccine. Three years after licensure, Black et al. reported in northern California a percent reduction of IPD of 93.7, 90.9 and 84.1% in children <1 year old, <2 years old and <5 years old, respectively and 98.8–100% if restricted to vaccine serotypes [23]. As a consequence, the overall incidence of occult bacteraemia among highly febrile young children in the era of pneumococcal conjugate vaccine has dropped below 1%. Stoll and Rubin reported that, of 329 blood cultures obtained from febrile children 2–36 months of age with fever ≥39 ◦ C, only three were positive for S. pneumoniae (0.91%, 95% CI: 0–1.9%) despite data suggesting a relatively low rate of PCV7 immunization [24]. In one child, the serotype was not included in the vaccine, and a second child had two episodes of bacteraemia 1 month apart. The serotype of this S. pneumoniae was included in the vaccine (serotype 4) but the child was not vaccinated. In contrast to the pneumococcal polysaccharide vaccine, PCV7 was also shown to affect nasopharyngeal carriage and transmission by decreasing the carriage of vaccine serotypes. Therefore by analysing the overall rate of IPD in populations where PCV7 was widely used, several studies have reported a strong herd effect. Indeed, the incidence of IPD decreased not only in vaccinated children but also in older children and in the adult population [22,23]. As of 2003, the total incidence
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of IPD in persons aged ≥65 years declined to 41.7 cases per 100 000 vs. 60 cases per 100 000 before the PCV7 era (30.5% decline) [25]. Significant reduction was also noted in people aged 20–39 and 40–64 years old. Because the burden of invasive pneumococcal disease is mainly in the adult population and taking into account the direct and indirect (herd effect) effectiveness of the PCV7, an analysis by the CDC revealed that, of the projected 29 599 cases of IPD due to vaccine type prevented in the USA by PCV7 in 2003 compared with 1998 and 1999, 9140 cases (31%) would be prevented by direct effect in vaccinated children and 20 459 cases (69%) by indirect effect of the vaccine across all ages. In other words, if you vaccinate one child with PCV7 you protect this child and two adults from invasive pneumococcal disease [26]. Another striking effect of PCV7 in the management of occult pneumococcal bacteraemia and other IPDs in children is its impact on antibiotic-resistant strains of S. pneumoniae. Worldwide, most antibiotic-resistant infections are caused by five of the seven serotypes included in PCV7 (6B, 9V, 14, 19F and 23F). In 1998, 24% of invasive pneumococcal isolates in the US were non-susceptible to penicillin, and these five serotypes accounted for 78% of such strains. As a consequence, we could expect that reduction of vaccine type IPD by vaccination should also reduce the percentage of circulating resistant strains of S. pneumoniae. Several recent studies addressing this question proved this to be true [23]. Kyaw et al. measured disease caused by antibioticnon-susceptible S. pneumoniae from 1996 through 2004 [27]. Isolates underwent serotyping and susceptibility testing. Results showed that overall, non-susceptible strains peaked in 1999 and decreased by 57% by 2004. This decline in the percentage of resistant strains occurred in all age groups, 81% in children aged less than 2 years, and 49% among persons 65 years or older. Restricting this analysis to vaccine-type S. pneumoniae the decline of non-susceptible strains was 98% and 79% for these two populations, respectively. However, the possibility that use of a vaccine that targets only seven of the 90 pneumococcal serotypes would lead to an increase in disease by non-vaccine types was addressed in the same study. The authors clearly showed an increase in the incidence of IPD caused by non-vaccine serotypes (so-called replacement strains) [27]. Indeed from 1999 to 2004 this incidence increased from 0.2 cases per 100 000 to 0.5 cases per 100 000 affecting all ages. Serotype 19A was particularly involved. Compared with an overall decline of IPD from 96.7 cases per 100 000 in 1998–1999 to 23.9 cases per 100 000 in 2003 among children aged <5 years, an increase of IPD due to non-vaccine serotypes of 0.2 cases to 0.5 cases per 100 000 does not bring into question the widespread use of this vaccine, but surveillance of this replacement phenomenon needs to be performed. Conjugate vaccines containing 11- and 13serotypes, including the replacement strains that emerged and strains that circulate in Europe and Asia, are under development.
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4. Conclusions S. pneumoniae bacteraemia is still a feared disease in young children because the clinical signs and symptoms are often indistinguishable from a banal viral disease, but if not treated can lead to severe disease such as sepsis or meningitis, which encompass substantial morbidity and mortality. Therefore, the conjugate vaccine that is now available against S. pneumoniae is a major advance in the struggle against this bacterium. Its immunogenicity in children from 2 months of age and its efficiency in decreasing nasopharyngeal carriage of vaccine serotypes have allowed a substantial and rapid decrease in invasive pneumococcal disease, not only in vaccinated children but also in older children and adults. Furthermore, because five serotypes very frequently associated with resistance to multiple antibiotics are included in the vaccine, an overall decrease in the incidence of invasive pneumococcal disease caused by drug-resistant strains has been noted. However, the serotype coverage of invasive S. pneumoniae strains included in the actual 7-valent vaccine is very variable from one country to another; in the range of 80–90% in the United States, but only 18–75% in Western Europe and around 45% in Asia. Moreover, replacement by non-vaccine serotypes has been noted in countries where the vaccine is widely used and this concern needs to be monitored carefully over the next few years. Finally, the global coverage of a population against invasive pneumococcal disease will depend on the vaccine uptake and a full immunisation of infants and children. Efforts should still be made in many countries to reach these objectives and to obtain results comparable to those in the United States. For all these reasons, in most countries the management of febrile children less than 36 months of age should not be modified before local assessment of the real impact of vaccination on the risk of developing a S. pneumoniae bacteraemia. Funding: No funding sources. Competing interests: None declared. Ethical approval: Not required.
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