Etiology

S. pneumoniae is a gram-positive, lancet-shaped, polysaccharide encapsulated diplococcus, occurring occasionally as individual cocci or in chains. More than 90 serotypes have been identified by type-specific capsular polysaccharides. Antisera to some pneumococcal polysaccharides cross react with other pneumococcal types, defining serogroups (e.g., 6A and 6B). Encapsulated strains cause most serious disease in humans. Capsular polysaccharides impede phagocytosis. Virulence is related in part to capsular size, but pneumococcal types with capsules of the same size can vary widely in virulence.

On solid media, S. pneumoniae forms unpigmented, umbilicated colonies surrounded by a zone of incomplete (α) hemolysis. S. pneumoniae is bile soluble (i.e., 10% deoxycholate) and optochin-sensitive. S. pneumoniae is closely related to the viridans groups of Streptococcus mitis, which typically overlap phenotypically with pneumococci. The conventional laboratory definition of pneumococci continues to rely on bile and optochin sensitivity, although considerable confusion occurs in distinguishing pneumococci and other α-hemolytic streptococci. Pneumococcal capsules can be microscopically visualized and typed by exposing organisms to type-specific antisera that combine with their unique capsular polysaccharide, rendering the capsule refractile (Quellung reaction). Specific antibodies to capsular polysaccharides confer protection on the host, promoting opsonization and phagocytosis. Additionally, CD4⁺ T cells have a direct role in antibody-independent immunity to pneumococcal nasopharyngeal colonization. Conjugated PCVs promote T-cell immunity and protect against pneumococcal colonization, in contrast to the pneumococcal polysaccharide vaccine (PPSV23) used primarily in adults that does not affect nasopharyngeal colonization.

Epidemiology

Most healthy individuals carry various S. pneumoniae serotypes in their upper respiratory tract; >90% of children between 6 mo and 5 yr of age harbor S. pneumoniae in the nasopharynx at some time. A single serotype usually is carried by a given individual for an extended period (45 days to 6 mo). Carriage does not consistently induce local or systemic immunity sufficient to prevent later reacquisition of the same serotype. Rates of pneumococcal carriage peak during the 1st and 2nd yr of life and decline gradually thereafter. Carriage rates are highest in institutional settings and during the winter, and rates are lowest in summer. Nasopharyngeal carriage of pneumococci is common among young children attending out-of-home care, with rates of 21-59% in point prevalence studies and 65% in longitudinal studies. During the past 4 decades, serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F have constituted the majority of invasive isolates in children in the U.S. and other developed countries; strains belonging to serotypes 6B, 9V, 14, and 19F frequently have reduced susceptibility to penicillin. Since licensure of the PCVs, the prevalence of carriage and infection with vaccine serotypes has substantially declined and a shift to increased carriage or infections with nonvaccine serotypes has occurred (Fig. 175-1). Indirect protection of unvaccinated persons has occurred since PCV introduction, and this herd protection is likely due to decreases in nasopharyngeal carriage of virulent pneumococcal vaccine serotypes.

Figure 175-1 Number of isolates from Streptococcus pneumoniae serogroups included in the heptavalent pneumococcal conjugate vaccine (PCV7 [Prevnar; Wyeth Lederle Vaccines]) and from nonvaccine serogroups recovered from children treated at Primary Children’s Medical Center (Salt Lake City, UT), by year.

(From Byington CL, Samore MH, Stoddard GJ, et al: Temporal trends of invasive disease due to Streptococcus pneumoniae among children in the intermountain west: emergence of nonvaccine serogroups, Clin Infect Dis 41:21–29, 2005.)

S. pneumoniae is the most frequent cause of bacteremia, bacterial pneumonia, and otitis media and the second most common cause of meningitis in children, next to Neisseria meningitidis. The decreased ability in children <2 yr of age to produce antibody against the T-cell independent polysaccharide antigens and the high prevalence of colonization may explain an increased susceptibility to pneumococcal infection and the decreased effectiveness of polysaccharide vaccines. Males are more commonly affected than females. Native American and African-American children have rates of invasive disease that are 2- to 10-fold higher than other healthy children. Prior to the introduction of PCVs into routine childhood immunization schedules, rates of invasive pneumococcal disease in the USA peaked at 6-11 mo of age, with attack rates of >540/100,000 in healthy children. Following the universal use of PCVs, rates of infection have fallen in both high-risk and healthy children. In Tennessee, peak rates of infection have fallen from 235/100,000 to 46/100,000 in children <2 yr of age and the proportion of penicillin-resistant strains in invasive disease have fallen from 59.8% to 30.4%.

Pneumococcal disease usually occurs sporadically but can be spread from person to person by respiratory droplet transmission. The frequency and severity of pneumococcal disease are increased in patients with sickle cell disease, asplenia, deficiencies in humoral (B cell) and complement-mediated immunity, HIV infection, certain malignancies (e.g., leukemia, lymphoma), chronic heart, lung, or renal disease (particularly the nephrotic syndrome), cerebrospinal fluid (CSF) leak, and cochlear implants. Other high-risk groups are noted in Table 175-1. S. pneumoniae is an important cause of secondary bacterial pneumonia in patients with influenza. During influenza epidemics and pandemics, most deaths result from bacterial pneumonia, and pneumococcus is the predominant bacterial pathogen isolated in this setting. Pneumococcal co-pathogenicity may be important in disease caused by other respiratory viruses as well.

Pathogenesis

Invasion of the host is affected by a number of factors. Nonspecific defense mechanisms, including the presence of other bacteria in the nasopharynx, may limit multiplication of pneumococci. Aspiration of secretions containing pneumococci is hindered by the epiglottic reflex and by respiratory epithelial cilia, which move infected mucus toward the pharynx. Similarly, normal ciliary flow of fluid from the middle ear through the eustachian tube and sinuses to the nasopharynx usually prevents infection with nasopharyngeal flora, including pneumococci. Interference with these normal clearance mechanisms by allergy, viral infection, or irritants (e.g., smoke) may allow colonization and subsequent infection with these organisms in otherwise normally sterile sites.

Virulent pneumococci are intrinsically resistant to phagocytosis by alveolar macrophages. Pneumococcal disease frequently is facilitated by viral respiratory tract infection, which may produce mucosal injury, diminish epithelial ciliary activity, and depress the function of alveolar macrophages and neutrophils. Phagocytosis may be impeded by respiratory secretions and alveolar exudate. In the lungs and other tissues, the spread of infection is facilitated by the antiphagocytic properties of the pneumococcal capsule. Surface fluids of the respiratory tract contain only small amounts of IgG and are deficient in complement. During inflammation, there is limited influx of IgG, complement, and neutrophils. Phagocytosis of bacteria by neutrophils may occur, but normal human serum may not opsonize pneumococci and facilitate phagocytosis by alveolar macrophages. In tissues, pneumococci multiply and spread through the lymphatics or bloodstream or, less commonly, by direct extension from a local site of infection (e.g., sinuses). In bacteremia, the severity of disease is related to the number of organisms in the bloodstream and to the integrity of specific host defenses. A poor prognosis correlates with very large numbers of pneumococci and high concentrations of capsular polysaccharide in the blood and CSF.

Invasive pneumococcal disease is 30- to 100-fold more prevalent in children with sickle cell disease and other hemoglobinopathies and in children with congenital or surgical asplenia than in the general population. This risk is greatest in infants <2 yr of age since at that age antibody production to most serotypes is poor. The increased frequency of pneumococcal disease in asplenic persons is related to both deficient opsonization of pneumococci as well as absence of clearance by the spleen of circulating bacteria. Children with sickle cell disease also have deficits in the antibody-independent properdin (alternative) pathway of complement activation, in addition to functional asplenia. Both complement pathways contribute to antibody-independent and antibody-dependent opsonophagocytosis of pneumococci. With advancing age (e.g., >5 yr), children with sickle cell disease produce anticapsular antibody, augmenting antibody-dependent opsonophagocytosis and greatly reducing, but not eliminating, the risk of severe pneumococcal disease. Deficiency of many of the complement components (e.g., C2 and C3) is associated with recurrent pyogenic infection, including S. pneumonia