Chapter 128. Pneumococcal Infections (Part 1) H pot

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).