Chapter 128. Pneumococcal Infections (Part 1) Harrison's Internal Medicine > Chapter 128. Pneumococcal Infections Pneumococcal Infections: Introduction Streptococcus pneumoniae (the pneumococcus) was recognized as a major cause of pneumonia in the 1880s. Although the name Diplococcus pneumoniae was originally assigned to the pneumococcus, the organism was renamed Streptococcus pneumoniae because, like other streptococci, it grows in chains in liquid medium. Widespread vaccination has reduced the incidence of pneumococcal infection, but this organism remains the principal bacterial cause of otitis media, acute purulent rhinosinusitis, pneumonia, and meningitis. Microbiology Pneumococci are identified in the clinical laboratory as catalase-negative, gram-positive cocci that grow in pairs or chains and cause α-hemolysis on blood agar. More than 98% of pneumococcal isolates are susceptible to ethylhydrocupreine (optochin), and virtually all pneumococcal colonies are dissolved by bile salts. Peptidoglycan and teichoic acid are the principal constituents of the pneumococcal cell wall, whose integrity depends on the presence of numerous peptide side chains cross-linked by the activity of enzymes such as trans- and carboxypeptidases. β-Lactam antibiotics inactivate these enzymes by covalently binding their active site. Unique to S. pneumoniae and present in all strains is C- substance ("cell-wall" substance), a polysaccharide consisting of teichoic acid with a phosphorylcholine residue. Surface-exposed choline residues serve as a site of attachment for potential virulence factors, such as pneumococcal surface protein A (PspA) and pneumococcal surface adhesin A (PsaA), which may prevent phagocytosis. Except for strains that cause conjunctivitis, nearly every clinical isolate of S. pneumoniae has a polysaccharide capsule, a structure that renders the bacteria virulent by preventing phagocytosis. All strains produce pneumolysin, a toxin that may cause many of the manifestations of pneumococcal infection. There are 90 serologically distinct capsules of S. pneumoniae. Serotyping remains clinically relevant because the activity of available vaccines is based on stimulating antibody to specific capsular polysaccharides. Epidemiology S. pneumoniae colonizes the nasopharynx and, on any single occasion, can be isolated from 5–10% of healthy adults and from 20–40% of healthy children. Once adults are colonized, organisms are likely to persist for 4–6 weeks but may be present for as long as 6 months. Pneumococci spread from one individual to another by direct or droplet transmission as a result of close contact; transmission may be enhanced by crowding or poor ventilation. Day-care centers have been a site of spread, especially of penicillin-resistant strains of serotypes 6B, 14, 19F, and 23F. Outbreaks of pneumococcal disease occur among adults in crowded living conditions—e.g., in military barracks, prisons, and shelters for the homeless—as well as among susceptible populations in settings such as nursing homes. The risk of pneumococcal pneumonia is generally not increased by contact in schools or workplaces (including hospitals). The incidence data provided below were obtained before widespread administration of pneumococcal conjugate vaccine to infants and children. (For the impact of widespread vaccination, see "Prevention," below.) In the absence of vaccination (which alters natural history), invasive pneumococcal disease is, by far, most prevalent among children <2 years old. The incidence is low among older children and adults <65 years of age but then rises in older adults. The fatality rate is also highest at the extremes of age. One surveillance study in the late 1980s found incidences of pneumococcal bacteremia among infants, young adults, and persons ≥70 years of age to be 160, 5, and 70 cases per 100,000 population, respectively. Most cases of pneumococcal bacteremia in adults are due to pneumonia, and there are 3–4 cases of nonbacteremic pneumonia for every bacteremic case. Thus an estimated 20 cases of pneumococcal pneumonia per 100,000 young adults and 280 cases per 100,000 persons over the age of 70 occur annually. The disease is more frequent among men than among women. The incidence of pneumococcal bacteremia among adults exhibits a distinct midwinter peak and a striking dip in summer; in children, the incidence is relatively constant throughout the year except for a marked dip in midsummer. For reasons that are unclear but probably multifactorial, Native Americans, Native Alaskans, and African Americans are more susceptible to invasive pneumococcal disease than are Caucasians. Natives of the Pacific Rim region are likewise more susceptible Pathogenetic Mechanisms Infection results when pneumococci colonizing the nasopharynx are carried into anatomically contiguous areas (e.g., the eustachian tubes, the nasal sinuses) and bacterial clearance is hindered (e.g., by mucosal edema due to allergy or viral infection). Clearly, the resistance of pneumococci to phagocytosis is central to their capacity to cause infection. Pneumonia ensues when organisms are inhaled or aspirated into the bronchioles or alveoli and are not cleared—especially, for example, if mucus production is increased and/or ciliary action is damaged by viral infection or by cigarette smoke or other toxic substances. Viral infection may also inhibit clearance by upregulating pneumocyte receptors that bind pneumococci. In normally sterile sites, such as the sinuses or the lungs, pneumococci activate complement, stimulating the production of cytokines that attract polymorphonuclear leukocytes (PMNs). The polysaccharide capsule, however, renders the pneumococci resistant to phagocytosis. In the absence of anticapsular antibody, a large bacterial inoculum and/or a compromise of phagocytic function allows the initiation of infection. Infection of the meninges, joints, bones, and peritoneal cavity may result from pneumococcal spread through the bloodstream, usually from a respiratory tract focus of infection. Unencapsulated pneumococci virtually never cause invasive disease, although they can cause conjunctivitis. Symptoms of disease are largely attributable to the inflammatory response, which may cause pain by increasing pressure (as in sinusitis or otitis media) or may interfere with vital bodily functions by preventing oxygenation of blood (as in pneumonia) or by inhibiting blood flow (as in vasculitis due to meningitis). Cell- wall constituents of S. pneumoniae, especially peptidoglycan, activate complement by the alternative pathway; the reaction between cell-wall structures and antibody (present in all humans) also activates the classic complement pathway. The result is the release of C5a, a potent attractant for PMNs, into the surrounding medium. Peptidoglycan can also directly stimulate the release of proinflammatory cytokines such as interleukin (IL) 1β, tumor necrosis factor (TNF) α, and IL-6. All pneumococci generate pneumolysin, a toxin that damages ciliary cells and PMNs and also activates the classic complement pathway. Injection of pneumolysin into the lungs of experimental animals produces the histologic features of pneumonia; in mice, immunization with this substance or challenge with genetically engineered mutants that do not produce it is associated with a significant reduction in virulence. Host Defense Mechanisms Mechanisms of host defense may be nonimmunologic or immunologic. Immunologic mechanisms may be natural (innate) or specific (humoral). . Chapter 128. Pneumococcal Infections (Part 1) Harrison's Internal Medicine > Chapter 128. Pneumococcal Infections Pneumococcal Infections: Introduction Streptococcus. polysaccharide consisting of teichoic acid with a phosphorylcholine residue. Surface-exposed choline residues serve as a site of attachment for potential virulence factors, such as pneumococcal surface. with this substance or challenge with genetically engineered mutants that do not produce it is associated with a significant reduction in virulence. Host Defense Mechanisms Mechanisms of host