Streptococcus pneumoniae: Epidemiology, Risk Factors, and Strategies for Prevention

Abstract and Introduction

Abstract

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia, meningitis, and bacteremia in children and adults. Invasive pneumococcal disease (IPD) primarily affects young children, older adults (> 65 years of age), and individuals with comorbidities or impaired immune systems. Case fatality rates range from 10 to 30% in adults with IPD but are much lower (<>

Introduction

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia (CAP) in adults, accounting for 30 to 70% of cases requiring hospitalization.^[1-4] A meta-analysis of 122 reports of CAP between 1966 and 1995 implicated S. pneumoniae in 66% of nearly 7000 cases with an established etiology.^[2] In addition, S. pneumoniae is the leading cause of bacteremia,^[5-7] meningitis,^[8] upper respiratory tract infections, and otitis media^[9] worldwide. Bacteremia is present in ∼20% of pneumococcal pneumonias in adults, with case-fatality rates of 10 to 30%.^[2,6,10-16] Mortality rates are much lower in children (<>[11,17,18] Invasive pneumococcal disease (IPD), defined as isolation of S. pneumoniae from a normally sterile site [e.g., blood; cerebrospinal fluid (CSF); surgical aspirate; pleural, pericardial, peritoneal, bone, or joint fluid],^[19] most frequently affects young children (particularly age 6 to 24 months), older adults (age ≥ 65 years), and immunocompromised individuals (children or adults).^[1,20] The World Health Organization (WHO) estimates that 1.6 million people, including up to 1 million children <>[21] with developing countries bearing the greatest burden.^[22] In North America and Europe, the annual incidence of pneumococcal bacteremia is 15 to 40/100,000 individuals.^[1,7,11,17] In the United States in 2003, 35,000 cases of IPD in adults ≥ age 18 led to 5600 deaths; 44% of cases and 60% of deaths were in adults ≥ 65 years of age (www.cdc.gov/abcs). The incidence is age dependent ( Table 1 ). In the United States, the annual incidence of IPD in children <> 65 years of age.^[11,17,23] Regional differences in the incidence of IPD have been noted.^[1,7,17,24] In Europe, the annual incidence of IPD in children <>[24-27] In the early to mid-1990s the reported incidence of pneumococcal bacteremia increased in several countries, including the United States,^[11,28] Belgium,^[25] Sweden,^[29,30] Norway,^[31] and Denmark.^[32] Following the introduction of pediatric heptavalent pneumococcal conjugate vaccine (PCV7) in the United States in February 2000, the incidence of IPD declined substantially in both children and nonvaccinated adults (by herd immunity).^{[7,15,23,33-36]} Unfortunately, the incidence of IPD due to non-PCV7 serotypes is increasing globally.^[37,38] Further, fluctuations in incidence of IPD within countries may occur due to clonal spread or other factors (in the absence of vaccine effect).^[27,30]

Clinical manifestations of pneumococcal infections are varied and include asymptomatic colonization,^[20,39] upper respiratory tract infections, otitis media,^[9,40] sinusitis,^[41] conjunctivitis,^[42,43] bacteremia (with or without a definite site of infection),^[5,6] pneumonia,^[1,6,10,11] empyema,^[44-47] meningitis,^[8,48] endocarditis,^[41,49-51] septic arthritis,^[52] cellulitis,^[53] and so forth. In young children, bacteremia without identifiable source accounts for 50 to 70% of episodes of IPD, pneumonia (15 to 25%), meningitis (4%), otitis media or miscellaneous sites (10%).^[54,55] In adults, pneumonia accounts for 50 to 80% of episodes of IPD. Other sites of infections include bacteremia without identifiable focus (15 to 20%), meningitis (4 to 8%), miscellaneous sites (2 to 5%).^[17,54-57]

Ecology of Streptococcus Pneumoniae Infections

The nasopharynx is the major ecological reservoir of S. pneumoniae; spread from the nasopharynx to lower respiratory tract or other sites may cause invasive disease.^[58] Children are the major carriers.^[39,59-62] Thirty to 50% of young children (<>S. pneumoniae in the nasopharynx,^[39,61,63] compared with carriage rates of only 4 to 12% in adults^[39,62,64] and 8.2% in adolescents.^[65] Higher rates of carriage (13 to 34%) were noted in adults in select populations.^[66-68] Young age (<>[39,59,60,63] Risk factors for NP carriage in adolescents or adults include acute upper respiratory tract infection,^[39,65] exposure to passive cigarette smoke,^[64,65] and asthma.^[65] Transmission from children to siblings, household contacts, or adults is the major cause of IPD.^[40,69,70] Interestingly, in Utah, children with IPD due to nonvaccine serotypes tended to be from larger households.^[71] Most children have at least one pneumococcal infection (typically of the middle ear) within the first 5 years of life.^[72-75] In subsequent years, pneumococcal infections are less common, due to acquisition of humoral immunity.^[72] Pneumococcal infections are more common in immunocompromised individuals (children or adults),^[76,77] older adults (age ≥ 65 years),^[78,79] or in the presence of comorbidities.^[55,79]

Pathogenesis of Streptococcus Pneumoniae Infections

NP carriage of S. pneumoniae is required for transmission of bacteria and for invasive disease.^[80] Pneumococci bind to mucosal epithelial cells of the nasopharynx.^[72] In normal healthy children, NP carriage of pneumococci is transient and is not associated with disease.^[21] However, disease is caused by contiguous spread to the sinuses or middle ear, aspiration into the lung, or invasion of the bloodstream.^[72] Progression to pneumonia requires additional factors (e.g., antecedent viral infections, lung injury, impaired host defenses, etc.). Clearance of pneumococci is facilitated by both humoral and cellular immune responses involving monocyte/macrophages, polymorphonuclear leukocytes (PMNs), anticapsular antibodies, and lymphocytes.^[72] Further, nonimmune factors (e.g., anatomical barriers, cilia, mucins, colectins, surfactant, etc.) are also critical to clear bacteria.^[81] Prognosis of pneumococcal infections depends upon both host- and organism-dependent factors.^[72]

The polysaccharide capsule serves as a major pathogenic factor for invasive disease by preventing phagocytosis.^[72] Humoral antibodies directed against the polysaccharide capsule usually develop within the first 2 years of life; colonization with specific serotypes may elicit serotype-specific humoral antibodies.^[72,82] Protection is serotype specific but some cross-serotype protection is found in some cases.^[80] However, these anticapsular antibodies (whether acquired naturally or by vaccination) provide incomplete protection against IPD.^[80,83,84] Antibodies to serotype 19F reduced colonization rates in some^[80] but not all studies.^[82] Additional serotype-independent factors are important in preventing or resolving pneumococcal disease and carriage.^[80] Components of the pneumococcal cell walls recruit PMNs to the lung, enhance permeability of alveolar epithelial cells, and stimulate cytokine release.^[72] The host's primary cellular immune response against S. pneumoniae is mediated by alveolar macrophages (AMs); neutrophils represent a second line of defense.^[85] The immune response against S. pneumoniae is complex, involving proinflammatory cytokines released by AMs [e.g., tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)],^[81,86] macrophage inflammatory protein-2 (MIP-2),^[81] upregulation of myriad cytokines and chemokines (e.g., IL-6, IL-8, and IL-18)^[81,87]], and adhesion molecules on endothelial cells.^[81] Toll-like receptors (TLRs), expressed on both immune and nonimmune cells, are important to recognize S. pneumoniae and promote bactericidal response by mononuclear cells.^[88] Further, granulocyte-colony stimulating factor (G-CSF) recruits and stimulates PMNs, facilitating phagocytosis and oxidative burst.^[81] T lymphocyte cells also play a role in eradicating pathogens from the alveolar spaces.^[81] Dendritic cells present the antigen to T cells, expanding CD4+ T cell responses, specifically T-helper 1 (Th1) and Th2 phenotypes.^[81] Th1 immunity, characterized by production of IL-2, IL-12, IL-18, granulocyte monocyte-colony stimulating factor (GM-CSF), and interferon-γ (INF-γ), is critical to the eradication of pneumococci.^[81] Interestingly, deficiency of IL-12 in humans has been associated with recurrent pneumococcal pneumonia.^[89] Th2 cells release cytokines that stimulate B cell antibody production, thereby facilitating humoral responses.^[81] Other cells/products critical to eradicating pneumococci include antibody- and complement-mediated opsonization; IL-1 receptor-associated kinase-4- and nuclear factor kappaB^[90]; and memory T cells (generated in the spleen).^[91] In summary, eradication of pneumococci is achieved by myriad interactions involving anatomical boundaries, diverse cells (immune and nonimmune), cytokines, chemokines, and humoral antibodies, and other factors that work in concert. Deficiency of specific immune components (e.g., asplenia, hypogammaglobulinemia, B cell dysfunction, etc.) can lead to recurrent or fatal pneumococcal infections. Further, prognosis of pneumococcal infections depends upon both host- and organism-dependent factors.^{[13,57,92,93]} Antiinflammatory cytokines (e.g., IL-4 and IL-10) have a role in harnessing (blunting) immune responses to infection and can be beneficial or detrimental depending upon the extent of infectious burden and host inflammatory response. Unregulated release of pneumococcal cell wall components during lysis can stimulate brisk inflammatory cytokine responses that may enhance pathological damage and heighten mortality.^[81] Optimal response to pneumococcal infections requires a carefully orchestrated and regulated response sufficient to kill the organism without causing excessive injury to the host.

Molecular Epidemiology: Importance of Serotypes

Virtually all strains of S. pneumoniae have a polysaccharide capsule, which is the basis for serotyping.^[80,94] Currently, 91 distinct capsular types have been identified.^[80] More than 99% of IPDs are caused by S. pneumoniae-containing capsules.^[42] Nonencapsulated strains are rare but were implicated in outbreaks of conjunctivitis in military trainees^[43] and college students.^[42] Globally, ∼20 serotypes account for > 80% of IPD in all age groups; 13 serotypes have been implicated in > 75% of IPD in children.^[21] The dominant serotypes associated with IPD worldwide include 14, 4, 1, 6A, 6B, 3, 8, 7F, 23F, 18C, 19F, and 9V.^[1,92,95] In young children, the number of serotypes is more limited, with types 6, 14, 18, 19, and 23F predominating.^[1] The reasons for the dominance of these serotypes in children, with their immature immune systems, is that these serotypes are less immunogenic than other types.^[1,78,96] In most series, more than 80% of IPDs were due to serotypes encompassed in the 23-valent PPV (pneumococcal polysaccharide vaccine), and 40 to 70% were due to serotypes included in the PCV7 (i.e., 4, 6B, 9V, 14, 18C, 19F, 23F).^{[1,15,54,80,92,96]} A major shift in the distribution of serotypes has been noted over time. In the beginning of the twentieth century, serotypes 1, 2, 3, and 5 accounted for up to 75% of bacteremic cases in the United States and Europe.^[1,97] Today, types 2 and 5 are rarely isolated in Western countries, and type 1 is uncommon.^[1] Instead, other serotypes have increased in prevalence. Interestingly, types 1 and 5 are common today in developing countries.^[1] Substantial differences in the distribution of serotypes have been noted in different geographical regions; further, the distribution may change over time.^[1,29] Serotype 3 has decreased in frequency over the past few decades, whereas type 14 has become more prevalent.^{[1,29,31,32,96,98]} In Sweden, the incidence of type 14 isolates increased threefold from 1987 to 1992; type 1 increased 10-fold from 1992 to 1997.^[30] The increase in type 14 reflected a hypervirulent clone that has also been found in the United States and Canada.^[30] Clonal expansion of other serotypes (e.g., type 1,^[99] serotypes 15 and 33^[38] and type 19A^[74,100-103]) has been noted in the United States. Changes in serotype distribution can be modified by antibiotic usage and vaccination patterns. In recent years (following the introduction of PCV7), nonvaccine serotypes are increasing in frequency.^[37,103,104] In a review of pneumococcal pneumonia in children in Utah, nonvaccine serotypes represented 49% of isolates from 1997 to 2000 and 88% of isolates from 2001 to 2006.^[37] Different serotypes exhibit differences in attack rate and colonization,^{[92,95,105-107]} case-fatality rates, and clinical expression of disease.^{[15,56,57,92,105]} In a study of pneumococcal pneumonia in children, serotype 3 was 15 times more likely to cause necrotizing pneumonia compared with other serotypes.^[37] Further, serotype 3 was associated with an increased risk of empyema and need for surgical procedures compared with other serotypes.^[37] Other investigators cited higher case fatality rates with IPD caused by serotype 3,^{[13,57,92,93]} although this was not a consistent finding.^[15,108] Sandgren et al evaluated 273 invasive (257 from adults) and 246 NP isolates (all from children) of S. pneumoniae in Stockholm in 1997.^[95] The isolates formed two major classes: one class comprised serotypes 1, 4, 7, and 9V and was highly clonally related; a second class caused invasive disease but also was common in carriage (including type 6A, 6B, 14, and 19F isolates) and was genetically more diverse.^[95] Serotypes 9V accounted for 7% of invasive isolates but only 2% of carrier isolates. By contrast, serotypes 6A and 19F accounted for 34% of isolates among carriers but only 3% of invasive isolates. Specific clones within the same serotype exhibited different abilities to cause invasive disease. Further, isolates belonging to the same clone that exhibited capsular switch displayed the same disease potential. In a subsequent study by these investigators, serotypes with the highest invasive potential (e.g., types 1 and 7F) were associated with low fatality rates, whereas serotypes 3, 6A, 6B, 11A, 19F, and 23F were associated with low invasive potential but caused more severe disease and increased mortality.^[56] Isolates with high invasive potential behave as primary pathogens, whereas strains with low invasive potential behave as opportunists (e.g., among patients with underlying disease).^[56] An international study from five countries from 1993 to 1995 found that serotype 14 was most common, but type 3 dominated in the fatal cases and in the United States and Spain, countries with the highest mortality rates.^[92] A study of 494 adults with IPD noted correlations between age and serotypes causing IPD.^[56] Serotype 1 was associated with IPD only among patients <> 65 years old (78%).^[56] In one study, serotype 12 was associated with lower mortality,^[57] whereas a prospective international study found no association with serotype and mortality when other risk factors were taken into account.^[15] Nonetheless, an association between serotype and enhanced virulence and severity of disease is plausible. In a murine model, cytokine proinflammatory responses were more robust in clones with less invasive potential,^[109] suggesting that differences in innate immune responses to specific clones (strains) may explain differences in the clinical expression/severity of disease. Serotype prevalence varies among geographic regions and may change over time in response to selective pressure or clonal spread.^{[30,95,110-113]} Further, capsular switching may occur, thus providing a survival advantage to the organism (by eluding capsular-specific opsonizing antibodies), and may facilitate survival of specific clones.^[56,95] In addition to capsular types, other properties of the organism (e.g., virulence factors, etc.)^[30,114] may influence disease severity and invasive potential. However, host factors are likely more important than serotype regarding severity of disease and mortality rates.^[15]

Risk Factors for Invasive Pneumococcal Disease

The incidence of IPD is much higher at extremes of age (<>[17,57,73-75,115,116] (Table 2), in patients with comorbidities or defects in immune defenses^{[1,17,57,71,76,115]} (Table 3 and Table 4), and in the winter months.^[1,117] In both children and adults, chronic illness is the strongest risk factor for IPD^[71,76] (Table 3). Invasive pneumococcal infections usually reflect transmission from NP carriage in children. Outbreaks of IPD may occur in crowded, closed settings such as schools,^[42] day care centers,^{[115,118,119]} households with multiple children,^{[40,75,115,120,121]} long-term care facilities (LTCFs),^[68,122-124] closed communities,^[125] military camps,^[43,126] shelters,^[127] jails,^[128] and hospitals.^{[119,129,130]} Interestingly, South African women infected with human immunodeficiency virus (HIV)were more likely to develop IPD with pediatric serotypes compared with HIV-infected men, likely because of women's closer proximity to small children.^[131] Widespread pneumococcal vaccination may reduce risk of IPD in closed populations^[68,132] and the community at large.^[23,55]

Infants <>[71,115,133,134] However, the risk of IPD is increased among preterm and low birth weight infants <>[115] In one study, day care attendance was associated with increased risk of IPD in infants between 6 and 23 months old, but not in older children (age 2 to 5 years).^[115] These trends reflect natural acquisition of immunity (usually by 2 to 3 years of age), that is durable. A history of tympanostomy tube was associated with an increased risk.^[71] In adults, advanced age predisposes to IPD, owing to the presence of comorbidities or immune senescence.^[17,76,124]

Ethnic and Socioeconomic Factors

Regional and racial differences in the incidence of IPD have been noted globally.^{[24,74,76,135]} Pneumococcal infections are more common in indigenous peoples of Alaska^[136-138] and the Canadian arctic,^[138] Inuits in Greenland,^[139] American Indians (White Mountain Apache and Navaho),^[82,140-142] blacks in the United States,^{[17,74,76,135]} Australian aborigines,^[143] Maoris of New Zealand,^[144] and Bedouins of Israel.^[145] Socioeconomic factors likely are responsible for the higher incidence in these groups, but genetics may play a contributory role. Genetic factors (e.g., polymorphisms) may play a role in susceptibility to IPD,^[146-149] but one large study from Denmark found no higher risk of IPD among relatives apart from risk associated with sharing the same household.^[75]

Risk Factors in Immunocompetent Individuals

Exposure to cigarette smoke and multiple children in the household are risk factors for IPD in healthy children.^[121] In otherwise immunocompetent adults, the incidence of IPD is increased with the following comorbidities: alcohol abuse,^{[76,142,150-152]} congestive heart failure,^{[76,135,142,153]} chronic lung disease,^[76,151,153] cigarette smoking,^{[151,153,154]} asthma,^[155] recent influenza infection,^[156] diabetes mellitus,^[76,135,157] institutionalization,^[124,153] neurological disorders,^[153] male gender,^[154] and black race^[17,76] (Table 2). Among immunocompetent adults 18 to 64 years of age, current cigarette smoking was the strongest risk factor for IPD.^[154] Further, a dose-response relation was found between number of cigarettes smoked and risk of IPD.^[154] Multiple comorbidities or age ≥ 65 years amplify the risk.^{[17,57,76,158]}

Immunosupressed Individuals

Patients with primary or acquired immune deficiencies have a heightened risk for IPD.^[76,90,135] The risk is highest among patients with B cell defects (due to intrinsic B cell anomaly or impaired T cell helper activity) or deficiencies of early components of the classical pathway of complement.^[90] Disorders associated with increased risk of IPD include asplenia,^[159-161] hemoglobinopathies (particularly sickle cell disease),^{[151,162-164]} hematological^[76,135,165] or solid^{[76,135,166,167]} malignancies,^[168-170] organ transplant recipients,^{[168,171-173]} HIV infection,^[151,174] and primary or acquired immunodeficiency states or receipt of immunosuppressive drugs (including corticosteroids).^[90,168-170] Each of these disorders is discussed separately in the sections that follow. Recurrent episodes of IPD are uncommon in immunocompetent hosts but may be observed in patients with severe immunodeficiency states (e.g., HIV infection or asplenia).^{[17, 54, 175-177]}.

Sickle Cell Disease

The incidence of IPD in children with sickle cell disease (SCD), particularly those with homozygous disease (SS), is 30- to 600-fold higher than in individuals of comparable age and race without SCD^{[151,162-164,178,179]} (Table 4). Pneumococcal septicemia and meningitis are important causes of death in SCD patients, with case/fatality rates of 15 to 35%.^{[164,180-186]} The risk of IPD is highest in children <>[162,164,181] Disease severity is usually worse in patients with homozygous (SS) and heterozygous (SC) disease. In one series, hypotension was more common with SS, whereas acute chest syndrome and otitis media were more common findings in patients with SC.^[164] The incidence of IPD and mortality due to bacterial infections in SCD has declined over the past 2 decades,^{[164,182,184,187]} likely reflecting the impact of penicillin prophylaxis, earlier recognition and treatment of infections,^{[181,182,186,188]} vaccines,^{[162,181,189,190]} and improved medical care.^[162]

However, even with prophylactic measures (e.g., antimicrobial prophylaxis and vaccination with the 23-valent polysaccharide pneumococcal vaccine (23PPV) at age ≥ 2 years), the incidence of IPD was 10-fold higher among SCD patients compared with controls.^[164] Further, many children with SCD do not receive antibiotic prophylaxis.^[163,188] Since 2001, the use of PCV7 has markedly reduced the incidence of IPD in children with SCD.^[162,179] From 1995 to 2000, the rate of IPD (per 1000 patient years) in children ages 0 to 10 years with SCD in Atlanta was 1.7; by 2001-02, the rate had declined to 0.5.^[179] In Tennessee, the rate of IPD decreased by 93.4% in SCD children ≤ 5 years old.^[162] Antibody responses are enhanced by using both PCV7 and 23PPV vaccines in children or young adults with SCD.^[191] Optimal duration of antibiotic prophylaxis is uncertain.^[163] Because the rate of IPD declines substantially in older children (> 5 years),^{[164,181,192]} it is reasonable to discontinue antibiotic prophylaxis after age 5 provided (1) patients have not had prior severe IPD, (2) vaccination has been administered, and (3) splenic function is adequate.^[193,194] Further, penicillin prophylaxis may not be necessary in countries or regions associated with a low rate of pneumococcal infections (e.g., Africa).^[195]

Splenectomy or Asplenia

Splenectomized patients or those with functional asplenia are at increased risk for life-threatening infections due to encapsulated bacteria (including pneumococcus).^{[160,169,170,196,197]} The risk of IPD after surgical splenectomy among nonvaccinated children ranges from 1 to 9%.^{[160,196,198]} Most IPD occur within 1 to 2 years of splenectomy,^[160] but the risk may persist for > 15 years in some cases.^[197] The incidence of IPD is even higher (up to 8.5%) among children with congenital asplenia.^{[160,161,199]} Further, the case-fatality rate of IPD is higher among asplenic children.^[160] Administering vaccines and prophylactic antibiotics reduces the risk.^[160,198] All asplenic children <>[160] However, response to vaccination may be blunted in asplenic patients.^[169] Antibiotic prophylaxis is warranted, but appropriate duration or therapy is controversial.

Risk in Solid and Hematologic Malignancies

The incidence of IPD is increased in patients with solid or hematologic malignancies^{[76,135,165-170,200]} ( Table 4 ). Kumashi et al reported 135 consecutive episodes of S. pneumoniae bacteremia in 122 cancer patients.^[166] Fifty-two percent of patients had hematological malignancies; 48% had solid cancers. Only 24 episodes (18%) occurred during neutropenia. Pneumonia was present in 67%; infected catheters accounted for 18% of episodes. Most (88%) episodes of bacteremia were community acquired. Overall, 19 patients (16%) died within 2 weeks of diagnosis. In a study of 56 cancer patients with pneumococcal bacteremia, the incidence was highest (> 1000 cases per 100,000) in the following groups: Hodgkin disease postsplenectomy, multiple myeloma, and chronic lymphocytic leukemia.^[167] In a recent study, German investigators cited a 10-fold increased incidence of IPD in children with acute lymphoblastic leukemia compared with the general pediatric population.^[200] This increased incidence of IPD reflects chemotherapy-induced immune aberrations, including: loss of B or T cell activity, neutropenia, chemotherapy-induced hyposplenism, impaired antibody responses to vaccines, and disruption of respiratory mucosa ciliary function.^[76,166]

Organ Transplant Recipients

The risk of IPD is much higher in recipients of hematopoietic stem cell (HSC)^{[168,172,173]} or solid organ^[171,201] transplants^{[168,172,173]} compared with healthy controls (Table 4). Infection risk depends upon intensity of immunosuppression and environmental factors and usually occurs > 3 months posttransplantation.^[171,172] The incidence is highest in allogeneic HSC recipients with chronic graft versus host disease (GVHD).^{[172,173,202-204]} Compared with the general population, the relative risk (RR) of IPD was 30.2 among HSC recipients^[172] and 12.8 among solid organ transplant (SOT) recipients residing in the same geographic region.^[205] Serotypes implicated among transplant recipients are similar to those reported in immunocompetent patients.^{[171,172,205]} Vaccination is important for all transplant recipients (SOT and HSC).^[206,207] Efficacy of vaccination may be blunted, however, by depletion of T and B cells among HSC recipients or the effects of immunosuppression on B cells in SOT recipients.^{[171,172,207,208]} The conjugate vaccine (PCV7) has enhanced immunogenicity compared with 23PPV and elicits a T cell and memory response.^[171,207] In a randomized trial, 3 doses of PCV7 administered at 3, 6, and 12 months after HSC conferred protection in most patients (72 to 100% for different serotypes) by 12 months after transplantation.^[209] Although the optimal vaccination schedule, type of vaccine, and efficacy among transplant recipients have not been validated in clinical trials,^[207] sequential doses of 23PPV at 12 and 24 months post-HSC transplant or combinations of both 23PPV and PCV7 are reasonable.^[172,207] For small children and patients (all ages) with chronic GVHD, administering 3 doses of PCV7 starting at 6 to 12 months after HSC is reasonable.^[207] Given the high risk of IPD among allogeneic HSC recipients and chronic GVHD, long-term antimicrobial prophylaxis may be warranted in this group.^[203,206] The choice of antibiotic depends on local antibiotic resistance patterns.^[207]

Human Immunodeficiency Virus Infected

In the era prior to highly active antiretroviral therapy (HAART), the rate of IPD among adults with HIV infection or acquired immunodeficiency syndrome (AIDS) in the United States or Europe was > 40 times higher than age-matched populations^{[19,151,174,210-214]} (Table 4). The incidence of IPD was highest among injection drug users with HIV.^[210,211] In HIV-infected children, the incidence rates of IPD are exceptionally high (ranging from 183 to 18,500 episodes per 100,000 child years.^[215-219] Recurrent episodes of IPD are more common among HIV-infected patients.^[54,210,214] A study of Gambian women with HIV/AIDS noted increased rates of NP colonization, often with pediatric serotypes.^[220] Surveillance data from the ABC Study in the United States noted that HIV-infected persons accounted for 15 to 20% of cases of IPD from 1998 to 1999.^[221]

Since the introduction of HAART, marked declines in the incidence of IPD^{[210-212,222-224]} have been noted in HIV-infected adults in developed countries (Table 4). Fewer data are available in children, but epidemiological studies cited severalfold reductions in the incidence of bacteremias^[225] or pneumonias^[225,226] in children between the pre-HAART and HAART eras.^[227] Unfortunately, in areas of the world with a large burden of HIV infection, the incidence of IPD may be increasing.^[228] Some studies reported lower mortality rates for IPD, including meningitis, among HIV-infected patients.^[210,229] This lower mortality rate may in part reflect a blunted inflammatory response to S. pneumoniae ^[230] and younger age of HIV-infected patients.^[210]

In the ABC surveillance study from 1998 to 1999, the distribution of serotypes causing IPD differed among adults with HIV/AIDS compared with adults with no underlying disease.^[221] The serotype distribution among HIV/AIDS patients was similar to those with hematogenous cancers.^[221] Similarly, a series of IPD in South Africa noted differences in serotypes and antimicrobial resistance patterns among HIV-infected and non-HIV-infected persons.^{[217,228,231]}

The use of trimethoprim/sulfamethoxazole (TMP/SMX) prophylaxis may select for more resistant pathogens,^[210,232] but prior use of TMP/SMX prophylaxis was not associated with TMP/SMX susceptibility in a large cohort (n = 416) of HIV-infected patients with pneumococcal bacteremia.^[221] However, in South African children with IPD, resistance to penicillin, TMP/SMX, and multidrug resistance were more common in HIV-infected children.^[217]

Pneumococcal vaccination is recommended for HIV-infected adults and adolescents with CD4+ lymphocyte counts > 200 cells/µL,^[233] but data supporting efficacy are limited.^[210,223] Immune deficits associated with HIV infection may dampen the antibody response to 23PPV.^{[230,234-236]} The use of 23PPV did not reduce the incidence of IPD, all-cause pneumonia, or mortality in a cohort of HIV-infected adults in Uganda.^[237] Retrospective studies in the United States suggested that 23PPV protects against IPD among certain groups of HIV-infected patients, specifically those with CD4 counts ≥ 200 cells/µL^[238] or ≥ 500 cells/µL^[212] at the time of vaccination or those receiving HAART.^[212,223] These studies were not controlled for comorbidities. A recent prospective study in the United States (the Veterans Aging Cohort 5-Site Study) found that vaccination with 23PPV reduced the risk of pneumonia in HIV-infected adults; current smoking, low hemoglobin level, and low CD4 cell count significantly increased the risk.^[239] Among non-HIV infected patients, vaccination with 23PPV did not confer protection (possibly because of lack of statistical power).^[239] Benefits associated with HAART may reflect its effects on improving B cell function^[240] and qualitative and quantitative responses to pneumococcal antigens.^[241] One randomized trial in HIV-infected adults found that vaccination with two injections of either PCV7 or 23PPV 2 months apart elicited higher antibody responses compared with placebo/23PPV.^[242] Vaccination with 23PPV after previous vaccination with PCV7 enhanced antibody response in HIV-infected adults.^[243] In HIV-infected children, PCV7 has been shown to be safe.^{[215,244,245]} PCV7 is immunogenic in HIV-infected children, but less so than in HIV-uninfected children.^{[215,244-246]} In children with HIV-infection, a positive correlation between antibody concentration elicited by PCV7 and duration of HAART was found.^[245] However, the functional activity of pneumococcal antibodies elicited by PCV7 was lower in HIV-infected compared with noninfected children.^[247] Clinical efficacy of PCV7 in HIV-infected patients remains uncertain. However, a South African trial noted significant reductions in IPD and pneumonia in HIV-infected children with a nine-valent vaccine.^[248] This effect was attenuated at 5 years compared with non-HIV-infected children.^[249] The impact of PCV7 in communities with high rates of HIV infections is not known. In the United States, the rate of IPD in HIV-infected adults (aged 18 to 64 years) declined by 19% from 1998-99 to 2003; vaccine-type IPD fell by 62% in this group.^[73] The optimal vaccination policy for HIV-infected persons has not been elucidated. However, universal vaccination of HIV-infected patients is reasonable to reduce colonization and infection.^[215]

Risk Factors for Mortality in Pneumococcal Pneumonia

Mortality for bacteremic pneumococcal pneumonia ranges from 10 to 30% in adults and <>[2,6,10,11,17,250] Case fatality rates for meningitis range from 16 to 37% in adults^[8,34] and 1 to 2.6% in children.^[34,251] Extrapulmonary manifestations will not be further addressed here. Mortality rates are much higher in the elderly and patients with comorbidities. Although disparate results have been noted, factors associated with higher mortality in bacteremic pneumococcal pneumonia include age (> 65 years),^{[2,5,11-13,15,252,253]} multilobar involvement,^{[2,12,14,252,254]} renal failure,^[11,12,17] leukopenia,^{[14,252,255-257]} alcohol abuse,^[6,257] immunosuppression,^[5] chronic cardiac disease,^[11,17] malignancy,^[17] chronic pulmonary disease,^[2,254] residence in a nursing home,^[2] serious underlying disease,^[5,14,15] need for intensive care unit (ICU)^[6] or mechanical ventilation,^[2,253] shock,^[14,257] high acute physiology scores,^[2] severity of disease,^[15] and treatment with parenteral nutrition.^[253] Discordant therapy was associated with higher mortality in some^[254,258] but not all^[5,259,260] studies. The impact of antimicrobial resistance and discordant antibiotic therapy is discussed in depth in the next article. HIV-infected patients have lower mortality in some studies,^[14] likely due to younger age. However, when patients were stratified by clinical status, patients with AIDS had far higher mortality than HIV-infected persons without AIDS.^{[17,174,211,215]} Interestingly, in a prospective, international study of IPD in adults, rigors and chest pain were associated with a lower mortality.^[15]

Clinical features of pneumococcal pneumonia are reviewed in detail elsewhere.^[1,6,10] We will limit our remarks to changes in the clinical presentation of pneumococcal pneumonia within the past few years (concomitant with the use of PCV7). Recent studies cited a marked increase in pneumococcal empyemas^{[44,47,261-263]} and necrotizing pneumonias^{[37,45,262,264]} in children, which reflects replacement by non-PCV7 serotypes (particularly serotypes 1, 3, and 19A).^{[37,261,265,266]}

Laboratory Diagnosis

Nonbacteremic pneumococcal pneumonia may be difficult to diagnose. Gram stains and microbiological cultures are the mainstays of diagnostic tests but are positive in fewer than 50% of cases of pneumococcal pneumonia.^[10] S. pneumoniae appear as lancet-shaped gram-positive diplococci. For bacteremic pneumococcal pneumonia in adults, sputum Gram stain and cultures had sensitivities of 80% and 93%, respectively, provided an adequate specimen was produced prior to therapy.^[10] In actual clinical practice, sensitivity is lower (<>[10,267,268] Rapid detection of pneumococcal antigens in urine,^[269,270] CSF,^[271] or pleural fluid^[272] may be helpful in selected patients (especially patients with meningitis or those who have received prior antibiotics).^[267] Latex agglutination tests are widely used to diagnose pneumococcal meningitis,^[271] but the value of these tests for urine or blood is controversial.^[267] An immunochromatographic test (NOW Streptococcus pneumoniae Antigen Test, Binax, Inc., Scarborough, ME), detects the C-polysaccharide wall antigen of S. pneumoniae.^[272,273] This urinary antigen test enables a rapid diagnosis (within 15 minutes) of pneumococcal pneumonia, but was less sensitive than sputum Gram stains in some studies.^[270,273] False positives, rare in adults,^[273] may be noted in children with NP carriage of S. pneumoniae.^[274,275] The combination of urinary antigen detection and sputum Gram stain increases the sensitivity^[270] but is expensive and time consuming in clinical practice. Binax NOW may be most useful for rapid diagnosis of pneumococcal meningitis, empyema, or pneumonia in high-risk patients in whom adequate sputum is unavailable.^{[270,272,273]} In children, Binax NOW lacks specificity and cannot distinguish colonization from infection.^[276] None of these techniques replaces culture, the only technique that allows antimicrobial susceptibility testing.

Pneumoccocal Vaccines

Currently, two pneumococcal vaccines are available. The 23-valent PPV (23 PPV), composed of purified free polysaccharides derived from the surface capsule of the bacterium, was introduced in 1983.^[277] These polysaccharide antigens elicit a T cell independent immune response and are therefore poor inducers of immunologic memory.^[1,245] Recommendations for using 23PPV in the United States are listed in Table 5.^[278] Indications for and extent of usage of 23PPV vary considerably among countries.^[277] 23PPV was efficacious and cost-effective in reducing the incidence of IPD in adults^[1,279,280] and may prevent outbreaks of pneumococcal pneumonia in institutional settings (e.g., nursing homes).^[68,132] The vaccine confers 60 to 80% protection against IPD in young healthy adults^[1] and elderly adults^[1,280-283] but is less effective in immunocompromised patients.^{[237,280,284]} Further, 23PPV is less effective in preventing nonbacteremic pneumonia^[282,285] or noninvasive infections (e.g., otitis media, conjunctivitis).^[286,287] Studies in elderly adults found that high serum antibody titers persist for 1 to 2 years^[288,289] but wane substantially over 5 years,^[290] as does the clinical effectiveness of the vaccine.^[280] In the United States, vaccination with 23PPV is recommended for all adults ≥ age 65 years and for high-risk individuals 2 to 64 years of age^[277] (Table 5). In Europe, indications for vaccination are variable among countries. In one survey, 17 of 21 countries recommended 23PPV for all adults ≥ 65 years of age.^[291] Recommendations for the use of PCV7 in Europe vary among countries.^[291] Revaccination for at risk adults after 5 years is safe and immunogenic,^[292,293] but vaccine responses are attenuated.^[294] Self-limited local reactions at the injection site following revaccination are more common (particularly in immunocompetent patients) but are not a contraindication to revaccination.^[21,295] Unfortunately, many patients who are candidates for 23PPV remain unvaccinated.^[296]

The 23PPV is poorly immunogenic in children ≤ age 2 years old, but PCV7 (introduced in the United States in February 2000) elicits good antibody responses in infants and young children.^[21,297] Conjugation of the capsular polysaccharide to a protein carrier elicits T cell responses that establish immunologic priming and a memory response.^[21,298] The serotypes incorporated into PCV7 include 4, 6B, 9V, 14, 18C, 19F, and 23F.^[299] In 2000 these seven serotypes accounted for > 80% of IPD in children in North America^[55,300] and were also prevalent in elderly adults.^[301] Currently, PCV7 is the only commercially available pneumococcal conjugate vaccine, but 10- and 13-valent conjugate vaccines may be available soon.^[21] As of January 2007, PCV7 was licensed in more than 70 countries.^[21] In 2000, recommendations for PCV7 use were published by the American Academy of Pediatrics Committee on Infectious Disease^[194] and Centers for Disease Control and Prevention^[297] (Table 6).^[302] In Europe, recommendations for the use of PCV7 in Europe vary among countries.^[291] In 1997, the WHO advised that PCV7 vaccination in children should be a priority, particularly in countries where mortality was high among children <>[21] Additionally, PCV7 should be prioritized in countries with a high prevalence of HIV, sickle cell disease, or other high-risk populations.^[21] Although precise schedules of vaccination differ, most countries administer 3 doses in infants within the first 6 months of life.^[299,303] In the United States, a booster dose of PCV7 is given at 12 to 15 months, and 23PPV is given at 2 years of age to broaden serotype coverage.^[297] Among developing countries, 3 doses of PCV7 to infants were immunogenic but data regarding clinical outcomes are limited.^[21] A 9-valent PCV that contains serotypes 1 and 5 in addition to the serotypes in PCV-7 was efficacious in Gambian children^[304] and HIV-infected children from South Africa,^[248] but it is not commercially available.^[300,305] The duration of protection against IPD due to PCV7 serotypes is at least 2 to 3 years, but probably is considerably longer.^[21] Although data are limited, PCV7 may have a role in elderly or immunocompromised adults. A recent randomized trial in vaccine naive adults ≥ 70 years of age assessed the impact of initial vaccination with either 23PPV or PCV7, followed by a booster vaccine (PCV7 or 23PPV) administered at 1 year. The seven serotypes encompassed by PCV7 were assessed. Initial vaccination with PCV7, followed by 23PPV at 1 year, elicited antibody responses that were comparable or higher than 23PPV alone. Importantly, initial vaccination with 23PPV followed by PCV7 induced lower antibody responses than PCV7/PCV7 or PCV7/23PPV. Thus 23PPV was ineffective as a priming dose and may induce hyporesponsiveness to subsequent booster doses (likely by depleting polysaccharide-specific memory B cells). Others have shown that revaccination with 23PPV after 5 years elicits lower antibody levels compared with the priming dose.^[294]

Following the use of PCV7 in children, marked declines in IPD were observed among all age groups (even in nonvaccinated adults) in North America,^{[21,23,35,36,55,57,138,299,305-307]} including high-risk^[189] and immunosuppressed^[57,162,308] individuals.^{[21,191,299,305,307]} In the United States, rates of vaccine-type IPD declined by 62% among people ≥ 5 years old between 1998-99 and 2003.^[307] In Canada, the rate of IPD in adults over 65 declined by 63% between 1998-2001 and 2004.^[309] Importantly, PCV7 reduced both colonization and infection with S. pneumoniae.^{[21,57,308,310,311]} By contrast, the incidence of IPD increased in Spain following the introduction of PCV7 and was associated with emergence of nonvaccine serotypes.^[112] In Alaskan native adults, colonization with vaccine-serotypes declined from 28 to 4.5% after introduction of PCV7 in children.^[312] Further, after 2001, the incidence of pneumococcal meningitis declined in the United States in both children and adults.^[251] The use of PCV7 in the United States led to reduction in racial disparity in IPD.^[74] However, in recent years, case-fatality rates have increased, reflecting a higher proportion of cases with comorbidities or non-PCV7 serotypes.^[57] In the United States and globally nonvaccine serotypes account for an increasing proportion of IPD, acute otitis media, and NP colonization.^{[36,38,55,73,101,102,112,137,307,313,314]} Ominously, in a study of Alaskan native infants, IPD due to nonvaccine serotypes increased by 140% since 2004 compared with the prevaccine period.^[137] During the same period (after 2004), IPD due to PCV7 serotypes declined by 96%.^[137] Further, the proportion of IPD cases with empyema increased from 2 to 13%.^[137] Several other studies cited an increased incidence of empyema in children in recent years due to nonvaccine serotypes.^{[37,44,47,261-263]} A prospective study of IPD from eight children's hospitals in the United States noted emergence of replacement serotypes 15 and 33; two dominant clones were observed.^[38] Currently, 19A has been the most common replacement serotype in the United States,^[74,101-103] whereas serotypes 1 and 5 have been most common in Spain.^[112] In some areas, this expansion has been clonal.^[112,137]

Vaccination strategies in both children and adults will continue to evolve. Serotypes affecting adults and children differ, mandating different strategies for specific populations. Changes in the distribution of serotypes following PCV7 will be a challenge for future vaccination strategies. Conjugate vaccines containing up to 13 serotypes are in development to improve coverage in adults and children on a global basis.^[21,315] It should also be emphasized that vaccinating elderly adults against influenza has reduced the risk of all-cause pneumonia,^[316,317] and may protect against IPD.^[318]

References

1. Ortqvist A, Hedlund J, Kalin M. Streptococcus pneumoniae: epidemiology, risk factors, and clinical features. Semin Respir Crit Care Med 2005; 26: 563-574
2. Kalin M, Ortqvist A, Almela M. Prospective study of prognostic factors in community-acquired bacteremic pneumococcal disease in 5 countries. J Infect Dis 2000; 182: 840-847
3. Fang GD, Fine M, Orloff J. New and emerging etiologies for community-acquired pneumonia with implications for therapy: a prospective multicenter study of 359 cases. Medicine (Baltimore) 1990; 69: 307-316
4. Bartlett JG, Mundy LM. Community-acquired pneumonia. N Engl J Med 1995; 333: 1618-1624
5. Yu VL, Chiou CC, Feldman C. An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome. Clin Infect Dis 2003; 37: 230-237
6. Musher DM, Alexandraki I, Graviss EA. Bacteremic and nonbacteremic pneumococcal pneumonia: a prospective study. Medicine (Baltimore) 2000; 79: 210-221
7. Shah SS, Ratner AJ. Trends in invasive pneumococcal disease-associated hospitalizations. Clin Infect Dis 2006; 42: e1-e5
8. Schuchat A, Robinson K, Wenger JD. Bacterial meningitis in the United States in 1995. Active Surveillance Team. N Engl J Med 1997; 337: 970-976
9. Klein JO. Otitis media. Clin Infect Dis 1994; 19: 823-833
10. Musher DM, Montoya R, Wanahita A. Diagnostic value of microscopic examination of Gram-stained sputum and sputum cultures in patients with bacteremic pneumococcal pneumonia. Clin Infect Dis 2004; 39: 165-169
11. Mufson MA, Stanek RJ. Bacteremic pneumococcal pneumonia in one American City: a 20-year longitudinal study, 1978-1997. Am J Med 1999; 107(1A): 34S-43S
12. Watanakunakorn C, Greifenstein A, Stroh K. Pneumococcal bacteremia in three community teaching hospitals from 1980 to 1989. Chest 1993; 103: 1152-1156
13. Mufson MA, Kruss DM, Wasil RE, Metzger WI. Capsular types and outcome of bacteremic pneumococcal disease in the antibiotic era. Arch Intern Med 1974; 134: 505-510
14. Pallares R, Linares J, Vadillo M. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med 1995; 333: 474-480
15. Alanee SR, McGee L, Jackson D. Association of serotypes of Streptococcus pneumoniae with disease severity and outcome in adults: an international study. Clin Infect Dis 2007; 45: 46-51
16. Ortqvist A. Pneumococcal disease in Sweden: experiences and current situation. Am J Med 1999; 107(1A): 44S-49S
17. Robinson KA, Baughman W, Rothrock G. Epidemiology of invasive Streptococcus pneumoniae infections in the United States, 1995-1998: opportunities for prevention in the conjugate vaccine era. JAMA 2001; 285: 1729-1735
18. Kaplan SL, Mason EOJr , Wald E. Six year multicenter surveillance of invasive pneumococcal infections in children. Pediatr Infect Dis J 2002; 21: 141-147
19. Schuchat A, Broome CV, Hightower A, Costa SJ, Parkin W. Use of surveillance for invasive pneumococcal disease to estimate the size of the immunosuppressed HIV-infected population. JAMA 1991; 265: 3275-3279
20. Lynch JPIII , Zhanel GG. Escalation of antimicrobial resistance among Streptococcus pneumoniae: implications for therapy. Semin Respir Crit Care Med 2005; 26: 575-616
21. Pneumococcal conjugate vaccine for childhood immunization-WHO position paper. Wkly Epidemiol Rec 2007; 82: 93-104
22. Scott JA. The preventable burden of pneumococcal disease in the developing world. Vaccine 2007; 25: 2398-2405
23. Whitney CG, Farley MM, Hadler J. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003; 348: 1737-1746
24. Jefferson T, Ferroni E, Curtale F, Giorgi Rossi P, Borgia P. Streptococcus pneumoniae in western Europe: serotype distribution and incidence in children less than 2 years old. Lancet Infect Dis 2006; 6: 405-410
25. Flamaing J, Verhaegen J, Peetermans WE. Streptococcus pneumoniae bacteraemia in Belgium: differential characteristics in children and the elderly population and implications for vaccine use. J Antimicrob Chemother 2002; 50: 43-50
26. Diez-Domingo J, Pereiro I, Morant A. Epidemiology of invasive Streptococcus pneumoniae infections in children in Spain, 1996-1998. J Infect 2002; 45: 139-143
27. Konradsen HB, Kaltoft MS. Invasive pneumococcal infections in Denmark from 1995 to 1999: epidemiology, serotypes, and resistance. Clin Diagn Lab Immunol 2002; 9: 358-365
28. Breiman RF, Spika JS, Navarro VJ, Darden PM, Darby CP. Pneumococcal bacteremia in Charleston County, South Carolina: a decade later. Arch Intern Med 1990; 150: 1401-1405
29. Hedlund J, Svenson SB, Kalin M. Incidence, capsular types, and antibiotic susceptibility of invasive Streptococcus pneumoniae in Sweden. Clin Infect Dis 1995; 21: 948-953
30. Henriques Normark B, Kalin M, Ortqvist A. Dynamics of penicillin-susceptible clones in invasive pneumococcal disease. J Infect Dis 2001; 184: 861-869
31. Magnus T, Andersen BM. Serotypes and resistance patterns of Streptococcus pneumoniae causing systemic disease in northern Norway. Eur J Clin Microbiol Infect Dis 1995; 14: 229-234
32. Nielsen SV, Henrichsen J. Incidence of invasive pneumococcal disease and distribution of capsular types of pneumococci in Denmark, 1989-94. Epidemiol Infect 1996; 117: 411-416
33. Hsu K, Pelton S, Karumuri S, Heisey-Grove D, Klein J. Population-based surveillance for childhood invasive pneumococcal disease in the era of conjugate vaccine. Pediatr Infect Dis J 2005; 24: 17-23
34. Haddy RI, Perry K, Chacko CE. Comparison of incidence of invasive Streptococcus pneumoniae disease among children before and after introduction of conjugated pneumococcal vaccine. Pediatr Infect Dis J 2005; 24: 320-323
35. Talbot TR, Poehling KA, Hartert TV. Reduction in high rates of antibiotic-nonsusceptible invasive pneumococcal disease in Tennessee after introduction of the pneumococcal conjugate vaccine. Clin Infect Dis 2004; 39: 641-648
36. Kaplan SL, Mason EOJr , Wald ER. Decrease of invasive pneumococcal infections in children among 8 children's hospitals in the United States after the introduction of the 7-valent pneumococcal conjugate vaccine. Pediatrics 2004; 113(3 Pt 1): 443-449
37. Bender JM, Ampofo K, Korgenski K. Pneumococcal necrotizing pneumonia in Utah: does serotype matter?. Clin Infect Dis 2008; 46: 1346-1352
38. Gonzalez BE, Hulten KG, Lamberth L, Kaplan SL, Mason EOJr . Streptococcus pneumoniae serogroups 15 and 33: an increasing cause of pneumococcal infections in children in the United States after the introduction of the pneumococcal 7-valent conjugate vaccine. Pediatr Infect Dis J 2006; 25: 301-305
39. Regev-Yochay G, Raz M, Dagan R. Nasopharyngeal carriage of Streptococcus pneumoniae by adults and children in community and family settings. Clin Infect Dis 2004; 38: 632-639
40. Shimada J, Yamanaka N, Hotomi M. Household transmission of Streptococcus pneumoniae among siblings with acute otitis media. J Clin Microbiol 2002; 40: 1851-1853
41. Gwaltney JMJr . Acute community-acquired sinusitis. Clin Infect Dis 1996; 23: 1209-1223quiz 1224-1225
42. Martin M, Turco JH, Zegans ME. An outbreak of conjunctivitis due to atypical Streptococcus pneumoniae. N Engl J Med 2003; 348: 1112-1121
43. Crum NF, Barrozo CP, Chapman FA, Ryan MA, Russell KL. An outbreak of conjunctivitis due to a novel unencapsulated Streptococcus pneumoniae among military trainees. Clin Infect Dis 2004; 39: 1148-1154
44. Byington CL, Spencer LY, Johnson TA. An epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema: risk factors and microbiological associations. Clin Infect Dis 2002; 34: 434-440
45. Hsieh YC, Hsueh PR, Lu CY, Lee PI, Lee CY, Huang LM. Clinical manifestations and molecular epidemiology of necrotizing pneumonia and empyema caused by Streptococcus pneumoniae in children in Taiwan. Clin Infect Dis 2004; 38: 830-835
46. Hardie W, Bokulic R, Garcia VF, Reising SF, Christie CD. Pneumococcal pleural empyemas in children. Clin Infect Dis 1996; 22: 1057-1063
47. Byington CL, Korgenski K, Daly J, Ampofo K, Pavia A, Mason EO. Impact of the pneumococcal conjugate vaccine on pneumococcal parapneumonic empyema. Pediatr Infect Dis J 2006; 25: 250-254
48. Stanek RJ, Mufson MA. A 20-year epidemiological study of pneumococcal meningitis. Clin Infect Dis 1999; 28: 1265-1272
49. Givner LB, Mason EOJr , Tan TQ. Pneumococcal endocarditis in children. Clin Infect Dis 2004; 38: 1273-1278
50. Martinez E, Miro JM, Almirante B. Effect of penicillin resistance of Streptococcus pneumoniae on the presentation, prognosis, and treatment of pneumococcal endocarditis in adults. Clin Infect Dis 2002; 35: 130-139
51. Lefort A, Mainardi JL, Selton-Suty C, Casassus P, Guillevin L, Lortholary O. Streptococcus pneumoniae endocarditis in adults: a multicenter study in France in the era of penicillin resistance (1991-1998). The Pneumococcal Endocarditis Study Group. Medicine (Baltimore) 2000; 79: 327-337
52. Ispahani P, Weston VC, Turner DP, Donald FE. Septic arthritis due to Streptococcus pneumoniae in Nottingham, United Kingdom, 1985-1998. Clin Infect Dis 1999; 29: 1450-1454
53. Capdevila O, Grau I, Vadillo M, Cisnal M, Pallares R. Bacteremic pneumococcal cellulitis compared with bacteremic cellulitis caused by Staphylococcus aureus and Streptococcus pyogenes. Eur J Clin Microbiol Infect Dis 2003; 22: 337-341
54. McEllistrem MC, Mendelsohn AB, Pass MA. Recurrent invasive pneumococcal disease in individuals with human immunodeficiency virus infection. J Infect Dis 2002; 185: 1364-1368
55. Albrich WC, Baughman W, Schmotzer B, Farley MM. Changing characteristics of invasive pneumococcal disease in Metropolitan Atlanta, Georgia, after introduction of a 7-valent pneumococcal conjugate vaccine. Clin Infect Dis 2007; 44: 1569-1576
56. Sjostrom K, Spindler C, Ortqvist A. Clonal and capsular types decide whether pneumococci will act as a primary or opportunistic pathogen. Clin Infect Dis 2006; 42: 451-459
57. Lexau CA, Lynfield R, Danila R. Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine. JAMA 2005; 294: 2043-2051
58. Bogaert D, De Groot R, Hermans PW. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect Dis 2004; 4: 144-154
59. Regev-Yochay G, Raz M, Shainberg B. Independent risk factors for carriage of penicillin-non-susceptible Streptococcus pneumoniae. Scand J Infect Dis 2003; 35: 219-222
60. Syrogiannopoulos GA, Grivea IN, Beratis NG. Resistance patterns of Streptococcus pneumoniae from carriers attending day-care centers in southwestern Greece. Clin Infect Dis 1997; 25: 188-194
61. Syrogiannopoulos GA, Katopodis GD, Grivea IN, Beratis NG. Antimicrobial use and serotype distribution of nasopharyngeal Streptococcus pneumoniae isolates recovered from Greek children younger than 2 years old. Clin Infect Dis 2002; 35: 1174-1182
62. Hussain M, Melegaro A, Pebody RG. A longitudinal household study of Streptococcus pneumoniae nasopharyngeal carriage in a UK setting. Epidemiol Infect 2005; 133: 891-898
63. Nunes S, Sa-Leao R, Carrico J. Trends in drug resistance, serotypes, and molecular types of Streptococcus pneumoniae colonizing preschool-age children attending day care centers in Lisbon, Portugal: a summary of 4 years of annual surveillance. J Clin Microbiol 2005; 43: 1285-1293
64. Greenberg D, Givon-Lavi N, Broides A, Blancovich I, Peled N, Dagan R. The contribution of smoking and exposure to tobacco smoke to Streptococcus pneumoniae and Haemophilus influenzae carriage in children and their mothers. Clin Infect Dis 2006; 42: 897-903
65. Cardozo DM, Nascimento-Carvalho CM, Andrade AL. Prevalence and risk factors for nasopharyngeal carriage of Streptococcus pneumoniae among adolescents. J Med Microbiol 2008; 57(Pt 2): 185-189
66. Brooks KJ, Paschane DM, Fisher DG, Orr SM. Pneumococcal carriage in an Alaskan drug-using population. Int J Circumpolar Health 1998; 57(Suppl 1): 260-264
67. Hansman D, Morris S, Gregory M, McDonald B. Pneumococcal carriage amongst Australian aborigines in Alice Springs, Northern Territory. J Hyg (Lond) 1985; 95: 677-684
68. Nuorti JP, Butler JC, Crutcher JM. An outbreak of multidrug-resistant pneumococcal pneumonia and bacteremia among unvaccinated nursing home residents. N Engl J Med 1998; 338: 1861-1868
69. Hoshino K, Watanabe H, Sugita R. High rate of transmission of penicillin-resistant Streptococcus pneumoniae between parents and children. J Clin Microbiol 2002; 40: 4357-4359
70. Muhlemann K, Matter HC, Tauber MG, Bodmer T. Nationwide surveillance of nasopharyngeal Streptococcus pneumoniae isolates from children with respiratory infection, Switzerland, 1998-1999. J Infect Dis 2003; 187: 589-596
71. Haddad MB, Porucznik CA, Joyce KE. Risk factors for pediatric invasive pneumococcal disease in the Intermountain West, 1996-2002. Ann Epidemiol 2008; 18: 139-146
72. Tuomanen EI, Austrian R, Masure HR. Pathogenesis of pneumococcal infection. N Engl J Med 1995; 332: 1280-1284
73. Flannery B, Heffernan RT, Harrison LH. Changes in invasive pneumococcal disease among HIV-infected adults living in the era of childhood pneumococcal immunization. Ann Intern Med 2006; 144: 1-9
74. Flannery B, Schrag S, Bennett NM. Impact of childhood vaccination on racial disparities in invasive Streptococcus pneumoniae infections. JAMA 2004; 291: 2197-2203
75. Hjuler T, Poulsen G, Wohlfahrt J, Kaltoft M, Biggar RJ, Melbye M. Genetic susceptibility to severe infection in families with invasive pneumococcal disease. Am J Epidemiol 2008; 167: 814-819
76. Kyaw MH, Rose CEJr , Fry AM. The influence of chronic illnesses on the incidence of invasive pneumococcal disease in adults. J Infect Dis 2005; 192: 377-386
77. Pallares R, Gudiol F, Linares J. Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci. N Engl J Med 1987; 317: 18-22
78. High KP. Pneumonia in older adults: new categories add complexity to diagnosis and care. Postgrad Med 2005; 118: 18-2025-28
79. Butler JC, Schuchat A. Epidemiology of pneumococcal infections in the elderly. Drugs Aging 1999; 15(Suppl 1): 11-19
80. Weinberger DM, Dagan R, Givon-Lavi N, Regev-Yochay G, Malley R, Lipsitch M. Epidemiologic evidence for serotype-specific acquired immunity to pneumococcal carriage. J Infect Dis 2008; 197: 1511-1518
81. Quinton L, Happel K, Gamble L, Nelson S. Pulmonary host defense: basic mechanisms and strategies for immunomodulation In: Niederman MS, Eds.; Severe Pneumonia: Lung Biology in Health and Science. Taylor and Francis Boca Raton: 2005, p. 383-411
82. Millar EV, O'Brien KL, Bronsdon MA. Anticapsular serum antibody concentration and protection against pneumococcal colonization among children vaccinated with 7-valent pneumococcal conjugate vaccine. Clin Infect Dis 2007; 44: 1173-1179
83. Malley R, Lipsitch M, Bogaert D. Serum antipneumococcal antibodies and pneumococcal colonization in adults with chronic obstructive pulmonary disease. J Infect Dis 2007; 196: 928-935
84. Goldblatt D, Hussain M, Andrews N. Antibody responses to nasopharyngeal carriage of Streptococcus pneumoniae in adults: a longitudinal household study. J Infect Dis 2005; 192: 387-393
85. Kirby AC, Raynes JG, Kaye PM. The role played by tumor necrosis factor during localized and systemic infection with Streptococcus pneumoniae. J Infect Dis 2005; 191: 1538-1547
86. O'Brien DP, Briles DE, Szalai AJ, Tu AH, Sanz I, Nahm MH. Tumor necrosis factor alpha receptor I is important for survival from Streptococcus pneumoniae infections. Infect Immun 1999; 67: 595-601
87. Lauw FN, Branger J, Florquin S. IL-18 improves the early antimicrobial host response to pneumococcal pneumonia. J Immunol 2002; 168: 372-378
88. Koedel U, Angele B, Rupprecht T. Toll-like receptor 2 participates in mediation of immune response in experimental pneumococcal meningitis. J Immunol 2003; 170: 438-444
89. Haraguchi S, Day NK, Nelson RPJr . Interleukin 12 deficiency associated with recurrent infections. Proc Natl Acad Sci U S A 1998; 95: 13125-13129
90. Picard C, Puel A, Bustamante J, Ku CL, Casanova JL. Primary immunodeficiencies associated with pneumococcal disease. Curr Opin Allergy Clin Immunol 2003; 3: 451-459
91. Kruetzmann S, Rosado MM, Weber H. Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J Exp Med 2003; 197: 939-945
92. Henriques B, Kalin M, Ortqvist A. Molecular epidemiology of Streptococcus pneumoniae causing invasive disease in 5 countries. J Infect Dis 2000; 182: 833-839
93. Martens P, Worm SW, Lundgren B, Konradsen HB, Benfield T. Serotype-specific mortality from invasive Streptococcus pneumoniae disease revisited. BMC Infect Dis 2004; 4: 21
94. Scott JA, Hall AJ, Dagan R. Serogroup-specific epidemiology of Streptococcus pneumoniae: associations with age, sex, and geography in 7,000 episodes of invasive disease. Clin Infect Dis 1996; 22: 973-981
95. Sandgren A, Sjostrom K, Olsson-Liljequist B. Effect of clonal and serotype-specific properties on the invasive capacity of Streptococcus pneumoniae. J Infect Dis 2004; 189: 785-796
96. Butler JC, Breiman RF, Lipman HB, Hofmann J, Facklam RR. Serotype distribution of Streptococcus pneumoniae infections among preschool children in the United States, 1978-1994: implications for development of a conjugate vaccine. J Infect Dis 1995; 171: 885-889
97. Austrian R. Some observations on the pneumococcus and on the current status of pneumococcal disease and its prevention. Rev Infect Dis 1981; 3(Suppl): S1-S17
98. Verhaegen J, Glupczynski Y, Verbist L. Capsular types and antibiotic susceptibility of pneumococci isolated from patients in Belgium with serious infections, 1980-1993. Clin Infect Dis 1995; 20: 1339-1345
99. Gonzalez BE, Hulten KG, Kaplan SL, Mason EOJr . Clonality of Streptococcus pneumoniae serotype 1 isolates from pediatric patients in the United States. J Clin Microbiol 2004; 42: 2810-2812
100. Toltzis P, Dul M, O'Riordan MA, Jacobs MR, Blumer J. Serogroup 19 pneumococci containing both mef and erm macrolide resistance determinants in an American city. Pediatr Infect Dis J 2006; 25: 19-24
101. Kyaw MH, Lynfield R, Schaffner W. Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae. N Engl J Med 2006; 354: 1455-1463
102. Pai R, Moore MR, Pilishvili T, Gertz RE, Whitney CG, Beall B. Postvaccine genetic structure of Streptococcus pneumoniae serotype 19A from children in the United States. J Infect Dis 2005; 192: 1988-1995
103. Messina AF, Katz-Gaynor K, Barton T. Impact of the pneumococcal conjugate vaccine on serotype distribution and antimicrobial resistance of invasive Streptococcus pneumoniae isolates in Dallas, TX, children from 1999 through 2005. Pediatr Infect Dis J 2007; 26: 461-467
104. Pelton SI, Huot H, Finkelstein JA. Emergence of 19A as virulent and multidrug resistant Pneumococcus in Massachusetts following universal immunization of infants with pneumococcal conjugate vaccine. Pediatr Infect Dis J 2007; 26: 468-472
105. Sleeman KL, Griffiths D, Shackley F. Capsular serotype-specific attack rates and duration of carriage of Streptococcus pneumoniae in a population of children. J Infect Dis 2006; 194: 682-688
106. Brueggemann AB, Peto TE, Crook DW, Butler JC, Kristinsson KG, Spratt BG. Temporal and geographic stability of the serogroup-specific invasive disease potential of Streptococcus pneumoniae in children. J Infect Dis 2004; 190: 1203-1211
107. Brueggemann AB, Griffiths DT, Meats E, Peto T, Crook DW, Spratt BG. Clonal relationships between invasive and carriage Streptococcus pneumoniae and serotype- and clone-specific differences in invasive disease potential. J Infect Dis 2003; 187: 1424-1432
108. McKenzie H, Reid N, Dijkhuizen RS. Clinical and microbiological epidemiology of Streptococcus pneumoniae bacteraemia. J Med Microbiol 2000; 49: 361-366
109. Sandgren A, Albiger B, Orihuela CJ, Tuomanen E, Normark S, Henriques-Normark B. Virulence in mice of pneumococcal clonal types with known invasive disease potential in humans. J Infect Dis 2005; 192: 791-800
110. Linares J, Pallares R, Alonso T. Trends in antimicrobial resistance of clinical isolates of Streptococcus pneumoniae in Bellvitge Hospital, Barcelona, Spain (1979-1990). Clin Infect Dis 1992; 15: 99-105
111. Feikin DR, Klugman KP. Historical changes in pneumococcal serogroup distribution: implications for the era of pneumococcal conjugate vaccines. Clin Infect Dis 2002; 35: 547-555
112. Munoz-Almagro C, Jordan I, Gene A, Latorre C, Garcia-Garcia JJ, Pallares R. Emergence of invasive pneumococcal disease caused by nonvaccine serotypes in the era of 7-valent conjugate vaccine. Clin Infect Dis 2008; 46: 174-182
113. Normark BH, Ortqvist A, Kalin M. Changes in serotype distribution may hamper efficacy of pneumococcal conjugate vaccines in children. Scand J Infect Dis 2001; 33: 848-850
114. Hava DL, Camilli A. Large-scale identification of serotype 4 Streptococcus pneumoniae virulence factors. Mol Microbiol 2002; 45: 1389-1406
115. Hjuler T, Wohlfahrt J, Simonsen J. Perinatal and crowding-related risk factors for invasive pneumococcal disease in infants and young children: a population-based case-control study. Clin Infect Dis 2007; 44: 1051-1056
116. Singleton RJ, Butler JC, Bulkow LR. Invasive pneumococcal disease epidemiology and effectiveness of 23-valent pneumococcal polysaccharide vaccine in Alaska native adults. Vaccine 2007; 25: 2288-2295
117. Mufson MA, Stanek RJ. Epidemiology of invasive Streptococcus pneumoniae infections and vaccine implications among children in a West Virginia community, 1978-2003. Pediatr Infect Dis J 2004; 23: 779-781
118. Cherian T, Steinhoff MC, Harrison LH, Rohn D, McDougal LK, Dick J. A cluster of invasive pneumococcal disease in young children in child care. JAMA 1994; 271: 695-697
119. Reichler MR, Rakovsky J, Slacikova M. Spread of multidrug-resistant Streptococcus pneumoniae among hospitalized children in Slovakia. J Infect Dis 1996; 173: 374-379
120. Leino T, Auranen K, Jokinen J, Leinonen M, Tervonen P, Takala AK. Pneumococcal carriage in children during their first two years: important role of family exposure. Pediatr Infect Dis J 2001; 20: 1022-1027
121. Pereiro I, Diez-Domingo J, Segarra L, Ballester A, Albert A, Morant A. Risk factors for invasive disease among children in Spain. J Infect 2004; 48: 320-329
122. Musher DM. Pneumococcal outbreaks in nursing homes. N Engl J Med 1998; 338: 1915-1916
123. Mannheimer SB, Riley LW, Roberts RB. Association of penicillin-resistant pneumococci with residence in a pediatric chronic care facility. J Infect Dis 1996; 174: 513-519
124. Kupronis BA, Richards CL, Whitney CG. Invasive pneumococcal disease in older adults residing in long-term care facilities and in the community. J Am Geriatr Soc 2003; 51: 1520-1525
125. Dagan R, Gradstein S, Belmaker I. An outbreak of Streptococcus pneumoniae serotype 1 in a closed community in southern Israel. Clin Infect Dis 2000; 30: 319-321
126. Gray GC, Mitchell BS, Tueller JE, Cross ER, Amundson DE. Pneumonia hospitalizations in the US Navy and Marine Corps: rates and risk factors for 6,522 admissions, 1981-1991. Am J Epidemiol 1994; 139: 793-802
127. Mercat A, Nguyen J, Dautzenberg B. An outbreak of pneumococcal pneumonia in two men's shelters. Chest 1991; 99: 147-151
128. Hoge CW, Reichler MR, Dominguez EA. An epidemic of pneumococcal disease in an overcrowded, inadequately ventilated jail. N Engl J Med 1994; 331: 643-648
129. Canet JJ, Juan N, Xercavins M, Freixas N, Garau J. Hospital-acquired pneumococcal bacteremia. Clin Infect Dis 2002; 35: 697-702
130. Rubins JB, Cheung S, Carson P, Rubins HB, Janoff EN. Identification of clinical risk factors for nosocomial pneumococcal bacteremia. Clin Infect Dis 1999; 29: 178-183
131. Buie KA, Klugman KP, von Gottberg A. Gender as a risk factor for both antibiotic resistance and infection with pediatric serogroups/serotypes, in HIV-infected and -uninfected adults with pneumococcal bacteremia. J Infect Dis 2004; 189: 1996-2000
132. Valenzuela MT, Altuzarra RH, Trucco OA. Immunogenicity of a 23-valent pneumococcal polysaccharide vaccine in elderly residents of a long-term care facility. Braz J Infect Dis 2007; 11: 322-326
133. Holmlund E, Quiambao B, Ollgren J, Nohynek H, Kayhty H. Development of natural antibodies to pneumococcal surface protein A, pneumococcal surface adhesin A and pneumolysin in Filipino pregnant women and their infants in relation to pneumococcal carriage. Vaccine 2006; 24: 57-65
134. Obaro SK, Deubzer HE, Newman VO, Adegbola RA, Greenwood BM, Henderson DC. Serotype-specific pneumococcal antibodies in breast milk of Gambian women immunized with a pneumococcal polysaccharide vaccine during pregnancy. Pediatr Infect Dis J 2004; 23: 1023-1029
135. Kyaw MH, Christie P, Clarke SC. Invasive pneumococcal disease in Scotland, 1999-2001: use of record linkage to explore associations between patients and disease in relation to future vaccination policy. Clin Infect Dis 2003; 37: 1283-1291
136. 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
137. Singleton RJ, Hennessy TW, Bulkow LR. Invasive pneumococcal disease caused by nonvaccine serotypes among Alaska native children with high levels of 7-valent pneumococcal conjugate vaccine coverage. JAMA 2007; 297: 1784-1792
138. Bruce MG, Deeks SL, Zulz T. International Circumpolar Surveillance System for invasive pneumococcal disease, 1999-2005. Emerg Infect Dis 2008; 14: 25-33
139. Christiansen J, Poulsen P, Ladefoged K. Invasive pneumococcal disease in Greenland. Scand J Infect Dis 2004; 36: 325-329
140. Millar EV, O'Brien KL, Watt JP. Effect of community-wide conjugate pneumococcal vaccine use in infancy on nasopharyngeal carriage through 3 years of age: a cross-sectional study in a high-risk population. Clin Infect Dis 2006; 43: 8-15
141. Watt JP, O'Brien KL, Benin AL. Invasive pneumococcal disease among Navajo adults, 1989-1998. Clin Infect Dis 2004; 38: 496-501
142. Watt JP, O'Brien KL, Benin AL. Risk factors for invasive pneumococcal disease among Navajo adults. Am J Epidemiol 2007; 166: 1080-1087
143. Roche P, Krause V. Invasive pneumococcal disease in Australia, 2001. Commun Dis Intell 2002; 26: 505-519
144. Voss L, Lennon D, Okesene-Gafa K, Ameratunga S, Martin D. Invasive pneumococcal disease in a pediatric population, Auckland, New Zealand. Pediatr Infect Dis J 1994; 13: 873-878
145. Fraser D, Givon-Lavi N, Bilenko N, Dagan R. A decade (1989-1998) of pediatric invasive pneumococcal disease in 2 populations residing in 1 geographic location: implications for vaccine choice. Clin Infect Dis 2001; 33: 421-427
146. Roy S, Knox K, Segal S. MBL genotype and risk of invasive pneumococcal disease: a case-control study. Lancet 2002; 359: 1569-1573
147. Yee AM, Phan HM, Zuniga R, Salmon JE, Musher DM. Association between FcgammaRIIa-R131 allotype and bacteremic pneumococcal pneumonia. Clin Infect Dis 2000; 30: 25-28
148. Moens L, Van Hoeyveld E, Peetermans WE, De Boeck C, Verhaegen J, Bossuyt X. Mannose-binding lectin genotype and invasive pneumococcal infection. Hum Immunol 2006; 67: 605-611
149. Schaaf BM, Boehmke F, Esnaashari H. Pneumococcal septic shock is associated with the interleukin-10-1082 gene promoter polymorphism. Am J Respir Crit Care Med 2003; 168: 476-480
150. Burman LA, Norrby R, Trollfors B. Invasive pneumococcal infections: incidence, predisposing factors, and prognosis. Rev Infect Dis 1985; 7: 133-142
151. Pastor P, Medley F, Murphy TV. Invasive pneumococcal disease in Dallas County, Texas: results from population-based surveillance in 1995. Clin Infect Dis 1998; 26: 590-595
152. Davidson M, Parkinson AJ, Bulkow LR, Fitzgerald MA, Peters HV, Parks DJ. The epidemiology of invasive pneumococcal disease in Alaska, 1986-1990-ethnic differences and opportunities for prevention. J Infect Dis 1994; 170: 368-376
153. Lipsky BA, Boyko EJ, Inui TS, Koepsell TD. Risk factors for acquiring pneumococcal infections. Arch Intern Med 1986; 146: 2179-2185
154. Nuorti JP, Butler JC, Farley MM. Cigarette smoking and invasive pneumococcal disease. Active Bacterial Core Surveillance Team. N Engl J Med 2000; 342: 681-689
155. Talbot TR, Hartert TV, Mitchel E. Asthma as a risk factor for invasive pneumococcal disease. N Engl J Med 2005; 352: 2082-2090
156. O'Brien KL, Walters MI, Sellman J. Severe pneumococcal pneumonia in previously healthy children: the role of preceding influenza infection. Clin Infect Dis 2000; 30: 784-789
157. Thomsen RW, Hundborg HH, Lervang HH, Johnsen SP, Schonheyder HC, Sorensen HT. Risk of community-acquired pneumococcal bacteremia in patients with diabetes: a population-based case-control study. Diabetes Care 2004; 27: 1143-1147
158. Loeb M. Pneumonia in older persons. Clin Infect Dis 2003; 37: 1335-1339
159. Bisharat N, Omari H, Lavi I, Raz R. Risk of infection and death among post-splenectomy patients. J Infect 2001; 43: 182-186
160. Schutze GE, Mason EOJr , Barson WJ. Invasive pneumococcal infections in children with asplenia. Pediatr Infect Dis J 2002; 21: 278-282
161. Gilbert B, Menetrey C, Belin V, Brosset P, de Lumley L, Fisher A. Familial isolated congenital asplenia: a rare, frequently hereditary dominant condition, often detected too late as a cause of overwhelming pneumococcal sepsis. Report of a new case and review of 31 others. Eur J Pediatr 2002; 161: 368-372
162. Halasa NB, Shankar SM, Talbot TR. Incidence of invasive pneumococcal disease among individuals with sickle cell disease before and after the introduction of the pneumococcal conjugate vaccine. Clin Infect Dis 2007; 44: 1428-1433
163. Wong WY, Overturf GD, Powars DR. Infection caused by Streptococcus pneumoniae in children with sickle cell disease: epidemiology, immunologic mechanisms, prophylaxis, and vaccination. Clin Infect Dis 1992; 14: 1124-1136
164. Adamkiewicz TV, Sarnaik S, Buchanan GR. Invasive pneumococcal infections in children with sickle cell disease in the era of penicillin prophylaxis, antibiotic resistance, and 23-valent pneumococcal polysaccharide vaccination. J Pediatr 2003; 143: 438-444
165. Carratala J, Roson B, Fernandez-Sevilla A, Alcaide F, Gudiol F. Bacteremic pneumonia in neutropenic patients with cancer: causes, empirical antibiotic therapy, and outcome. Arch Intern Med 1998; 158: 868-872
166. Kumashi P, Girgawy E, Tarrand JJ, Rolston KV, Raad II, Safdar A. Streptococcus pneumoniae bacteremia in patients with cancer: disease characteristics and outcomes in the era of escalating drug resistance (1998-2002). Medicine (Baltimore) 2005; 84: 303-312
167. Chou MY, Brown AE, Blevins A, Armstrong D. Severe pneumococcal infection in patients with neoplastic disease. Cancer 1983; 51: 1546-1550
168. Youssef S, Rodriguez G, Rolston KV, Champlin RE, Raad II, Safdar A. Streptococcus pneumoniae infections in 47 hematopoietic stem cell transplantation recipients: clinical characteristics of infections and vaccine-breakthrough infections, 1989-2005. Medicine (Baltimore) 2007; 86: 69-77
169. Castagnola E, Fioredda F. Prevention of life-threatening infections due to encapsulated bacteria in children with hyposplenia or asplenia: a brief review of current recommendations for practical purposes. Eur J Haematol 2003; 71: 319-326
170. Altamura M, Caradonna L, Amati L, Pellegrino NM, Urgesi G, Miniello S. Splenectomy and sepsis: the role of the spleen in the immune-mediated bacterial clearance. Immunopharmacol Immunotoxicol 2001; 23: 153-161
171. Schutze GE, Mason EOJr , Wald ER. Pneumococcal infections in children after transplantation. Clin Infect Dis 2001; 33: 16-21
172. Kumar D, Humar A, Plevneshi A. Invasive pneumococcal disease in adult hematopoietic stem cell transplant recipients: a decade of prospective population-based surveillance. Bone Marrow Transplant 2008; 41: 743-747
173. Engelhard D, Cordonnier C, Shaw PJ. Early and late invasive pneumococcal infection following stem cell transplantation: a European Bone Marrow Transplantation survey. Br J Haematol 2002; 117: 444-450
174. Redd SC, Rutherford GWIII , Sande MA. The role of human immunodeficiency virus infection in pneumococcal bacteremia in San Francisco residents. J Infect Dis 1990; 162: 1012-1017
175. King MD, Whitney CG, Parekh F, Farley MM. Recurrent invasive pneumococcal disease: a population-based assessment. Clin Infect Dis 2003; 37: 1029-1036
176. Coccia MR, Facklam RR, Saravolatz LD, Manzor O. Recurrent pneumococcal bacteremia: 34 episodes in 15 patients. Clin Infect Dis 1998; 26: 982-985
177. Font B, Lliminana C, Fontanals D, Pineda V, Segura F. Eleven-year study of recurrent pneumococcal bacteremia. Eur J Clin Microbiol Infect Dis 2001; 20: 636-638
178. Barrett-Connor E. Bacterial infection and sickle cell anemia. An analysis of 250 infections in 166 patients and a review of the literature. Medicine (Baltimore) 1971; 50: 97-112
179. Adamkiewicz TV, Silk BJ, Howgate J. Effectiveness of the 7-valent pneumococcal conjugate vaccine in children with sickle cell disease in the first decade of life. Pediatrics 2008; 121: 562-569
180. Chesney PJ, Wilimas JA, Presbury G. Penicillin- and cephalosporin-resistant strains of Streptococcus pneumoniae causing sepsis and meningitis in children with sickle cell disease. J Pediatr 1995; 127: 526-532
181. Hord J, Byrd R, Stowe L, Windsor B, Smith-Whitley K. Streptococcus pneumoniae sepsis and meningitis during the penicillin prophylaxis era in children with sickle cell disease. J Pediatr Hematol Oncol 2002; 24: 470-472
182. Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients. Medicine (Baltimore) 2005; 84: 363-376
183. Miller ST, Sleeper LA, Pegelow CH. Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med 2000; 342: 83-89
184. Leikin SL, Gallagher D, Kinney TR, Sloane D, Klug P, Rida W. Mortality in children and adolescents with sickle cell disease. Cooperative Study of Sickle Cell Disease. Pediatrics 1989; 84: 500-508
185. Knight-Madden J, Serjeant GR. Invasive pneumococcal disease in homozygous sickle cell disease: Jamaican experience 1973-1997. J Pediatr 2001; 138: 65-70
186. Gaston MH, Verter JI, Woods G. Prophylaxis with oral penicillin in children with sickle cell anemia: a randomized trial. N Engl J Med 1986; 314: 1593-1599
187. Quinn CT, Rogers ZR, Buchanan GR. Survival of children with sickle cell disease. Blood 2004; 103: 4023-4027
188. Sox CM, Cooper WO, Koepsell TD, DiGiuseppe DL, Christakis DA. Provision of pneumococcal prophylaxis for publicly insured children with sickle cell disease. JAMA 2003; 290: 1057-1061
189. O'Brien KL, Swift AJ, Winkelstein JA. Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM(197) among infants with sickle cell disease. Pneumococcal Conjugate Vaccine Study Group. Pediatrics 2000; 106: 965-972
190. Reinert P, Benkerrou M, de Montalembert M. Immunogenicity and safety of a pneumococcal conjugate 7-valent vaccine in infants with sickle cell disease. Pediatr Infect Dis J 2007; 26(12): 1105-1109
191. Vernacchio L, Neufeld EJ, MacDonald K. Combined schedule of 7-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal vaccine in children and young adults with sickle cell disease. J Pediatr 1998; 133: 275-278
192. Wong WY, Powars DR, Chan L, Hiti A, Johnson C, Overturf G. Polysaccharide encapsulated bacterial infection in sickle cell anemia: a thirty year epidemiologic experience. Am J Hematol 1992; 39: 176-182
193. Falletta JM, Woods GM, Verter JI. Discontinuing penicillin prophylaxis in children with sickle cell anemia. Prophylactic Penicillin Study II. J Pediatr 1995; 127: 685-690
194. American Academy of Pediatrics. Committee on Infectious Diseases. Policy statement: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis. Pediatrics 2000; 106(2 Pt 1): 362-366
195. Kizito ME, Mworozi E, Ndugwa C, Serjeant GR. Bacteraemia in homozygous sickle cell disease in Africa: is pneumococcal prophylaxis justified?. Arch Dis Child 2007; 92: 21-23
196. Chilcote RR, Baehner RL, Hammond D. Septicemia and meningitis in children splenectomized for Hodgkin's disease. N Engl J Med 1976; 295: 798-800
197. Foss Abrahamsen A, Hoiby EA, Hannisdal E. Systemic pneumococcal disease after staging splenectomy for Hodgkin's disease 1969-1980 without pneumococcal vaccine protection: a follow-up study 1994. Eur J Haematol 1997; 58: 73-77
198. Konradsen HB, Henrichsen J. Pneumococcal infections in splenectomized children are preventable. Acta Paediatr Scand 1991; 80: 423-427
199. Waldman JD, Rosenthal A, Smith AL, Shurin S, Nadas AS. Sepsis and congenital asplenia. J Pediatr 1977; 90: 555-559
200. Meisel R, Toschke AM, Heiligensetzer C, Dilloo D, Laws HJ, von Kries R. Increased risk for invasive pneumococcal diseases in children with acute lymphoblastic leukaemia. Br J Haematol 2007; 137: 457-460
201. Amber IJ, Gilbert EM, Schiffman G, Jacobson JA. Increased risk of pneumococcal infections in cardiac transplant recipients. Transplantation 1990; 49: 122-125
202. Haddad PA, Repka TL, Weisdorf DJ. Penicillin-resistant Streptococcus pneumoniae septic shock and meningitis complicating chronic graft versus host disease: a case report and review of the literature. Am J Med 2002; 113: 152-155
203. Kulkarni S, Powles R, Treleaven J. Chronic graft versus host disease is associated with long-term risk for pneumococcal infections in recipients of bone marrow transplants. Blood 2000; 95: 3683-3686
204. Rege K, Mehta J, Treleaven J. Fatal pneumococcal infections following allogeneic bone marrow transplant. Bone Marrow Transplant 1994; 14: 903-906
205. Kumar D, Humar A, Plevneshi A. Invasive pneumococcal disease in solid organ transplant recipients-10-year prospective population surveillance. Am J Transplant 2007; 7: 1209-1214
206. Rizzo JD, Wingard JR, Tichelli A. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2006; 12: 138-151
207. Ljungman P, Engelhard D, de la Camara R. Vaccination of stem cell transplant recipients: recommendations of the Infectious Diseases Working Party of the EBMT. Bone Marrow Transplant 2005; 35: 737-746
208. Nordoy T, Husebekk A, Aaberge IS. Humoral immunity to viral and bacterial antigens in lymphoma patients 4-10 years after high-dose therapy with ABMT. Serological responses to revaccinations according to EBMT guidelines. Bone Marrow Transplant 2001; 28: 681-687
209. Molrine DC, Antin JH, Guinan EC. Donor immunization with pneumococcal conjugate vaccine and early protective antibody responses following allogeneic hematopoietic cell transplantation. Blood 2003; 101: 831-836
210. Jordano Q, Falco V, Almirante B. Invasive pneumococcal disease in patients infected with HIV: still a threat in the era of highly active antiretroviral therapy. Clin Infect Dis 2004; 38: 1623-1628
211. Nuorti JP, Butler JC, Gelling L, Kool JL, Reingold AL, Vugia DJ. Epidemiologic relation between HIV and invasive pneumococcal disease in San Francisco County, California. Ann Intern Med 2000; 132: 182-190
212. Dworkin MS, Ward JW, Hanson DL, Jones JL, Kaplan JE. Pneumococcal disease among human immunodeficiency virus-infected persons: incidence, risk factors, and impact of vaccination. Clin Infect Dis 2001; 32: 794-800
213. Frankel RE, Virata M, Hardalo C, Altice FL, Friedland G. Invasive pneumococcal disease: clinical features, serotypes, and antimicrobial resistance patterns in cases involving patients with and without human immunodeficiency virus infection. Clin Infect Dis 1996; 23: 577-584
214. Boschini A, Smacchia C, Di Fine M. Community-acquired pneumonia in a cohort of former injection drug users with and without human immunodeficiency virus infection: incidence, etiologies, and clinical aspects. Clin Infect Dis 1996; 23: 107-113
215. Bliss SJ, O'Brien KL, Janoff EN. The evidence for using conjugate vaccines to protect HIV-infected children against pneumococcal disease. Lancet Infect Dis 2008; 8: 67-80
216. Dankner WM, Lindsey JC, Levin MJ. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J 2001; 20: 40-48
217. Madhi SA, Petersen K, Madhi A, Wasas A, Klugman KP. Impact of human immunodeficiency virus type 1 on the disease spectrum of Streptococcus pneumoniae in South African children. Pediatr Infect Dis J 2000; 19: 1141-1147
218. Madhi SA, Petersen K, Madhi A, Khoosal M, Klugman KP. Increased disease burden and antibiotic resistance of bacteria causing severe community-acquired lower respiratory tract infections in human immunodeficiency virus type 1-infected children. Clin Infect Dis 2000; 31: 170-176
219. Laufer MK, van Oosterhout JJ, Perez MA. Observational cohort study of HIV-infected African children. Pediatr Infect Dis J 2006; 25: 623-627
220. Gill CJ, Mwanakasale V, Fox MP. Impact of human immunodeficiency virus infection on Streptococcus pneumoniae colonization and seroepidemiology among Zambian women. J Infect Dis 2008; 197: 1000-1005
221. Fry AM, Facklam RR, Whitney CG, Plikaytis BD, Schuchat A. Multistate evaluation of invasive pneumococcal diseases in adults with human immunodeficiency virus infection: serotype and antimicrobial resistance patterns in the United States. J Infect Dis 2003; 188: 643-652
222. Heffernan RT, Barrett NL, Gallagher KM. Declining incidence of invasive Streptococcus pneumoniae infections among persons with AIDS in an era of highly active antiretroviral therapy, 1995-2000. J Infect Dis 2005; 191: 2038-2045
223. Lopez-Palomo C, Martin-Zamorano M, Benitez E. Pneumonia in HIV-infected patients in the HAART era: incidence, risk, and impact of the pneumococcal vaccination. J Med Virol 2004; 72: 517-524
224. Grau I, Pallares R, Tubau F. Epidemiologic changes in bacteremic pneumococcal disease in patients with human immunodeficiency virus in the era of highly active antiretroviral therapy. Arch Intern Med 2005; 165: 1533-1540
225. Gona P, Van Dyke RB, Williams PL. Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA 2006; 296: 292-300
226. Viani RM, Araneta MR, Deville JG, Spector SA. Decrease in hospitalization and mortality rates among children with perinatally acquired HIV type 1 infection receiving highly active antiretroviral therapy. Clin Infect Dis 2004; 39: 725-731
227. Nachman S, Gona P, Dankner W. The rate of serious bacterial infections among HIV-infected children with immune reconstitution who have discontinued opportunistic infection prophylaxis. Pediatrics 2005; 115: e488-e494
228. Karstaedt AS, Khoosal M, Crewe-Brown HH. Pneumococcal bacteremia in adults in Soweto, South Africa, during the course of a decade. Clin Infect Dis 2001; 33: 610-614
229. Almirante B, Saballs M, Ribera E. Favorable prognosis of purulent meningitis in patients infected with human immunodeficiency virus. Clin Infect Dis 1998; 27: 176-180
230. Janoff EN, O'Brien J, Thompson P. Streptococcus pneumoniae colonization, bacteremia, and immune response among persons with human immunodeficiency virus infection. J Infect Dis 1993; 167: 49-56
231. Crewe-Brown HH, Karstaedt AS, Saunders GL. Streptococcus pneumoniae blood culture isolates from patients with and without human immunodeficiency virus infection: alterations in penicillin susceptibilities and in serogroups or serotypes. Clin Infect Dis 1997; 25: 1165-1172
232. Wininger DA, Fass RJ. Impact of trimethoprim-sulfamethoxazole prophylaxis on etiology and susceptibilities of pathogens causing human immunodeficiency virus-associated bacteremia. Antimicrob Agents Chemother 2002; 46: 594-597
233. Masur H, Kaplan JE, Holmes KK. Guidelines for preventing opportunistic infections among HIV-infected persons-2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. Ann Intern Med 2002; 137(5 Pt 2): 435-478
234. Amendola A, Tanzi E, Zappa A. Safety and immunogenicity of 23-valent pneumococcal polysaccharide vaccine in HIV-1 infected former drug users. Vaccine 2002; 20: 3720-3724
235. Huo Z, Miles J, Harris T, Riches P. Effect of Pneumovax II vaccination in high-risk individuals on specific antibody and opsonic capacity against specific and non-specific antigen. Vaccine 2002; 20: 3532-3534
236. French N, Gilks CF, Mujugira A, Fasching C, O'Brien J, Janoff EN. Pneumococcal vaccination in HIV-1-infected adults in Uganda: humoral response and two vaccine failures. AIDS 1998; 12: 1683-1689
237. French N, Nakiyingi J, Carpenter LM. 23-valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults: double-blind, randomised and placebo controlled trial. Lancet 2000; 355: 2106-2111
238. Gebo KA, Moore RD, Keruly JC, Chaisson RE. Risk factors for pneumococcal disease in human immunodeficiency virus-infected patients. J Infect Dis 1996; 173: 857-862
239. Rodriguez-Barradas MC, Goulet J, Brown S. Impact of pneumococcal vaccination on the incidence of pneumonia by HIV infection status among patients enrolled in the Veterans Aging Cohort 5-Site Study. Clin Infect Dis 2008; 46: 1093-1100
240. Moir S, Ogwaro KM, Malaspina A. Perturbations in B cell responsiveness to CD4+ T cell help in HIV-infected individuals. Proc Natl Acad Sci U S A 2003; 100: 6057-6062
241. Rodriguez-Barradas MC, Alexandraki I, Nazir T. Response of human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy to vaccination with 23-valent pneumococcal polysaccharide vaccine. Clin Infect Dis 2003; 37: 438-447
242. Feikin DR, Elie CM, Goetz MB. Randomized trial of the quantitative and functional antibody responses to a 7-valent pneumococcal conjugate vaccine and/or 23-valent polysaccharide vaccine among HIV-infected adults. Vaccine 2001; 20: 545-553
243. Kroon FP, van Dissel JT, Ravensbergen E, Nibbering PH, van Furth R. Enhanced antibody response to pneumococcal polysaccharide vaccine after prior immunization with conjugate pneumococcal vaccine in HIV-infected adults. Vaccine 2000; 19: 886-894
244. Nachman S, Kim S, King J. Safety and immunogenicity of a heptavalent pneumococcal conjugate vaccine in infants with human immunodeficiency virus type 1 infection. Pediatrics 2003; 112(1 Pt 1): 66-73
245. Abzug MJ, Pelton SI, Song LY. Immunogenicity, safety, and predictors of response after a pneumococcal conjugate and pneumococcal polysaccharide vaccine series in human immunodeficiency virus-infected children receiving highly active antiretroviral therapy. Pediatr Infect Dis J 2006; 25: 920-929
246. Spoulou VI, Tsoumas DL, Papaevangelou VG, Mostrou GI, Theodoridou MC. Immunogenicity and immunological memory induced by a 7-valent pneumococcal CRM197 conjugate vaccine in symptomatic HIV-1 infected children. Vaccine 2005; 23: 5289-5293
247. Madhi SA, Kuwanda L, Cutland C, Holm A, Kayhty H, Klugman KP. Quantitative and qualitative antibody response to pneumococcal conjugate vaccine among African human immunodeficiency virus-infected and uninfected children. Pediatr Infect Dis J 2005; 24: 410-416
248. Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003; 349: 1341-1348
249. Madhi SA, Adrian P, Kuwanda L. Long-term immunogenicity and efficacy of a 9-valent conjugate pneumococcal vaccine in human immunodeficient virus infected and non-infected children in the absence of a booster dose of vaccine. Vaccine 2007; 25: 2451-2457
250. Laurichesse H, Romaszko JP, Nguyen LT. Clinical characteristics and outcome of patients with invasive pneumococcal disease, Puy-de-Dome, France, 1994-1998. Eur J Clin Microbiol Infect Dis 2001; 20: 299-308
251. Tsai CJ, Griffin MR, Pekka Nuorti J, Grijalva CG. Changing epidemiology of pneumococcal meningitis after the introduction of pneumococcal conjugate vaccine in the United States. Clin Infect Dis 2008; 46: 1664-1672
252. Hook EWIII , Horton CA, Schaberg DR. Failure of intensive care unit support to influence mortality from pneumococcal bacteremia. JAMA 1983; 249: 1055-1057
253. Farinas-Alvarez C, Farinas MC, Garcia-Palomo JD. Prognostic factors for pneumococcal bacteremia in a university hospital. Eur J Clin Microbiol Infect Dis 2000; 19: 733-741
254. Lujan M, Gallego M, Fontanals D, Mariscal D, Rello J. Prospective observational study of bacteremic pneumococcal pneumonia: Effect of discordant therapy on mortality. Crit Care Med 2004; 32: 625-631
255. Torres JM, Cardenas O, Vasquez A, Schlossberg D. Streptococcus pneumoniae bacteremia in a community hospital. Chest 1998; 113: 387-390
256. Austrian R, Gold J. Pneumococcal bacteremia with especial reference to bacteremic pneumococcal pneumonia. Ann Intern Med 1964; 60: 759-776
257. Perlino CA, Rimland D. Alcoholism, leukopenia, and pneumococcal sepsis. Am Rev Respir Dis 1985; 132: 757-760
258. Metlay JP, Hofmann J, Cetron MS. Impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia. Clin Infect Dis 2000; 30: 520-528
259. Rothermel CD. Penicillin and macrolide resistance in pneumococcal pneumonia: does in vitro resistance affect clinical outcomes?. Clin Infect Dis 2004; 38(Suppl 4): S346-S349
260. Aspa J, Rajas O, Rodriguez de Castro F. Drug-resistant pneumococcal pneumonia: clinical relevance and related factors. Clin Infect Dis 2004; 38: 787-798
261. Calbo E, Diaz A, Canadell E. Invasive pneumococcal disease among children in a health district of Barcelona: early impact of pneumococcal conjugate vaccine. Clin Microbiol Infect 2006; 12: 867-872
262. Lin CJ, Chen PY, Huang FL, Lee T, Chi CS, Lin CY. Radiographic, clinical, and prognostic features of complicated and uncomplicated community-acquired lobar pneumonia in children. J Microbiol Immunol Infect 2006; 39: 489-495
263. Ramphul N, Eastham KM, Freeman R. Cavitatory lung disease complicating empyema in children. Pediatr Pulmonol 2006; 41: 750-753
264. Hsieh YC, Hsiao CH, Tsao PN. Necrotizing pneumococcal pneumonia in children: the role of pulmonary gangrene. Pediatr Pulmonol 2006; 41: 623-629
265. Eastham KM, Freeman R, Kearns AM. Clinical features, aetiology and outcome of empyema in children in the north east of England. Thorax 2004; 59: 522-525
266. Byington CL, Samore MH, Stoddard GJ. Temporal trends of invasive disease due to Streptococcus pneumoniae among children in the intermountain west: emergence of nonvaccine serogroups. Clin Infect Dis 2005; 41: 21-29
267. Werno AM, Murdoch DR. Medical microbiology: laboratory diagnosis of invasive pneumococcal disease. Clin Infect Dis 2008; 46: 926-932
268. Roson B, Carratala J, Verdaguer R, Dorca J, Manresa F, Gudiol F. Prospective study of the usefulness of sputum Gram stain in the initial approach to community-acquired pneumonia requiring hospitalization. Clin Infect Dis 2000; 31: 869-874
269. Marcos MA, Jimenez de Anta MT, de la Bellacasa JP. Rapid urinary antigen test for diagnosis of pneumococcal community-acquired pneumonia in adults. Eur Respir J 2003; 21: 209-214
270. Murdoch DR, Laing RT, Mills GD. Evaluation of a rapid immunochromatographic test for detection of Streptococcus pneumoniae antigen in urine samples from adults with community-acquired pneumonia. J Clin Microbiol 2001; 39: 3495-3498
271. Samra Z, Shmuely H, Nahum E, Paghis D, Ben-Ari J. Use of the NOW Streptococcus pneumoniae urinary antigen test in cerebrospinal fluid for rapid diagnosis of pneumococcal meningitis. Diagn Microbiol Infect Dis 2003; 45: 237-240
272. Le Monnier A, Carbonnelle E, Zahar JR. Microbiological diagnosis of empyema in children: comparative evaluations by culture, polymerase chain reaction, and pneumococcal antigen detection in pleural fluids. Clin Infect Dis 2006; 42: 1135-1140
273. Roson B, Fernandez-Sabe N, Carratala J. Contribution of a urinary antigen assay (Binax NOW) to the early diagnosis of pneumococcal pneumonia. Clin Infect Dis 2004; 38: 222-226
274. Hamer DH, Egas J, Estrella B, MacLeod WB, Griffiths JK, Sempertegui F. Assessment of the Binax NOW Streptococcus pneumoniae urinary antigen test in children with nasopharyngeal pneumococcal carriage. Clin Infect Dis 2002; 34: 1025-1028
275. Adegbola RA, Obaro SK, Biney E, Greenwood BM. Evaluation of Binax now Streptococcus pneumoniae urinary antigen test in children in a community with a high carriage rate of pneumococcus. Pediatr Infect Dis J 2001; 20: 718-719
276. Dowell SF, Garman RL, Liu G, Levine OS, Yang YH. Evaluation of Binax NOW, an assay for the detection of pneumococcal antigen in urine samples, performed among pediatric patients. Clin Infect Dis 2001; 32: 824-825
277. Fedson DS. Pneumococcal vaccination in the United States and 20 other developed countries, 1981-1996. Clin Infect Dis 1998; 26: 1117-1123
278. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1997; 46(RR-8): 1-24
279. Sisk JE, Moskowitz AJ, Whang W. Cost-effectiveness of vaccination against pneumococcal bacteremia among elderly people. JAMA 1997; 278: 1333-1339
280. Shapiro ED, Berg AT, Austrian R. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med 1991; 325: 1453-1460
281. Butler JC, Breiman RF, Campbell JF, Lipman HB, Broome CV, Facklam RR. Pneumococcal polysaccharide vaccine efficacy: an evaluation of current recommendations. JAMA 1993; 270: 1826-1831
282. Honkanen PO, Keistinen T, Miettinen L. Incremental effectiveness of pneumococcal vaccine on simultaneously administered influenza vaccine in preventing pneumonia and pneumococcal pneumonia among persons aged 65 years or older. Vaccine 1999; 17: 2493-2500
283. Ortqvist A, Hedlund J, Burman LA. Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Swedish Pneumococcal Vaccination Study Group. Lancet 1998; 351: 399-403
284. Breiman RF, Keller DW, Phelan MA. Evaluation of effectiveness of the 23-valent pneumococcal capsular polysaccharide vaccine for HIV-infected patients. Arch Intern Med 2000; 160: 2633-2638
285. Jackson LA, Neuzil KM, Yu O. Effectiveness of pneumococcal polysaccharide vaccine in older adults. N Engl J Med 2003; 348: 1747-1755
286. Simberkoff MS, Cross AP, Al-Ibrahim M. Efficacy of pneumococcal vaccine in high-risk patients. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986; 315: 1318-1327
287. Watson L, Wilson BJ, Waugh N. Pneumococcal polysaccharide vaccine: a systematic review of clinical effectiveness in adults. Vaccine 2002; 20: 2166-2173
288. Brandao AP, de Oliveira TC, de Cunto Brandileone MC, Goncalves JE, Yara TI, Simonsen V. Persistence of antibody response to pneumococcal capsular polysaccharides in vaccinated long term-care residents in Brazil. Vaccine 2004; 23: 762-768
289. Rubins JB, Puri AK, Loch J. Magnitude, duration, quality, and function of pneumococcal vaccine responses in elderly adults. J Infect Dis 1998; 178: 431-440
290. Konradsen HB. Quantity and avidity of pneumococcal antibodies before and up to five years after pneumococcal vaccination of elderly persons. Clin Infect Dis 1995; 21: 616-620
291. Pebody RG, Leino T, Nohynek H, Hellenbrand W, Salmaso S, Ruutu P. Pneumococcal vaccination policy in Europe. Euro Surveill 2005; 10: 174-178
292. Torling J, Hedlund J, Konradsen HB, Ortqvist A. Revaccination with the 23-valent pneumococcal polysaccharide vaccine in middle-aged and elderly persons previously treated for pneumonia. Vaccine 2003; 22: 96-103
293. Willis BC, Ndiaye SM, Hopkins DP, Shefer A. Improving influenza, pneumococcal polysaccharide, and hepatitis B vaccination coverage among adults aged <>
294. Jackson LA, Neuzil KM, Nahm MH. Immunogenicity of varying dosages of 7-valent pneumococcal polysaccharide-protein conjugate vaccine in seniors previously vaccinated with 23-valent pneumococcal polysaccharide vaccine. Vaccine 2007; 25: 4029-4037
295. Jackson LA, Benson P, Sneller VP. Safety of revaccination with pneumococcal polysaccharide vaccine. JAMA 1999; 281: 243-248
296. Kyaw MH, Greene CM, Schaffner W. Adults with invasive pneumococcal disease: missed opportunities for vaccination. Am J Prev Med 2006; 31: 286-292
297. Advisory Committee on Immunization Practice. Preventing pneumococcal disease among infants and young children: recommendations of the Advisory Committee on Immunization Practice (ACIP). MMWR Recomm Rep 2000; 49(RR-9): 1-35
298. Shinefield HR, Black S, Ray P. Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers. Pediatr Infect Dis J 1999; 18: 757-763
299. Black S, Shinefield H, Fireman B. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J 2000; 19: 187-195
300. Pelton SI. Replacement pneumococcal disease in perspective. Clin Infect Dis 2008; 46: 1353-1355
301. Feikin DR, Klugman KP, Facklam RR, Zell ER, Schuchat A, Whitney CG. Increased prevalence of pediatric pneumococcal serotypes in elderly adults. Clin Infect Dis 2005; 41: 481-487
302. Updated Recommendations from the Advisory Committee on Immunization Practices (ACIP) for use of 7-valent pneumococcal conjugate vaccine (PCV7) in children aged 24-59 months who are not completed vaccinated. MMWR Morb Mortal Wkly Rep 2008; 57: 343-344
303. Reinert P, Guy M, Girier B. The safety and immunogenicity of an heptavalent pneumococcal polysaccharide conjugate vaccine (Prevenar) administered in association with a whole-cell pertussis-based pediatric combination vaccine (DTP-IPV/PRP-T) to French infants with a two-, three-, and four-month schedule [in French]. Arch Pediatr 2003; 10: 1048-1055
304. Cutts FT, Zaman SM, Enwere G. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in the Gambia: randomised, double-blind, placebo-controlled trial. Lancet 2005; 365: 1139-1146
305. Lipsitch M, O'Neill K, Cordy D. Strain characteristics of Streptococcus pneumoniae carriage and invasive disease isolates during a cluster-randomized clinical trial of the 7-valent pneumococcal conjugate vaccine. J Infect Dis 2007; 196: 1221-1227
306. Poehling KA, Talbot TR, Griffin MR. Invasive pneumococcal disease among infants before and after introduction of pneumococcal conjugate vaccine. JAMA 2006; 295: 1668-1674
307. 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 Morb Mortal Wkly Rep 2005; 54(36): 893-897
308. Black SB, Shinefield HR, Hansen J, Elvin L, Laufer D, Malinoski F. Postlicensure evaluation of the effectiveness of seven valent pneumococcal conjugate vaccine. Pediatr Infect Dis J 2001; 20: 1105-1107
309. Kellner JD, Church DL, MacDonald J, Tyrrell GJ, Scheifele D. Progress in the prevention of pneumococcal infection. CMAJ 2005; 173: 1149-1151
310. Steenhoff AP, Shah SS, Ratner AJ, Patil SM, McGowan KL. Emergence of vaccine-related pneumococcal serotypes as a cause of bacteremia. Clin Infect Dis 2006; 42: 907-914
311. Cohen R, Levy C, de La Rocque F. Impact of pneumococcal conjugate vaccine and of reduction of antibiotic use on nasopharyngeal carriage of nonsusceptible pneumococci in children with acute otitis media. Pediatr Infect Dis J 2006; 25: 1001-1007
312. Hammitt LL, Bruden DL, Butler JC. Indirect effect of conjugate vaccine on adult carriage of Streptococcus pneumoniae: an explanation of trends in invasive pneumococcal disease. J Infect Dis 2006; 193: 1487-1494
313. Eskola J, Kilpi T, Palmu A. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001; 344: 403-409
314. Porat N, Arguedas A, Spratt BG. Emergence of penicillin-nonsusceptible Streptococcus pneumoniae clones expressing serotypes not present in the antipneumococcal conjugate vaccine. J Infect Dis 2004; 190: 2154-2161
315. de Roux A, Schmoele-Thoma B, Siber GR. Comparison of pneumococcal conjugate polysaccharide and free polysaccharide vaccines in elderly adults: conjugate vaccine elicits improved antibacterial immune responses and immunological memory. Clin Infect Dis 2008; 46: 1015-1023
316. Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med 1994; 331: 778-784
317. Gross PA, Hermogenes AW, Sacks HS, Lau J, Levandowski RA. The efficacy of influenza vaccine in elderly persons: a meta-analysis and review of the literature. Ann Intern Med 1995; 123: 518-527
318. Christenson B, Hedlund J, Lundbergh P, Ortqvist A. Additive preventive effect of influenza and pneumococcal vaccines in elderly persons. Eur Respir J 2004; 23: 363-368

Source : http://www.medscape.com/viewarticle/702635