Group B Streptococcus

Etiology

Group B streptococci are facultative anaerobic gram-positive cocci that form chains or diplococci in broth and small, gray-white colonies on solid medium. GBS is definitively identified by demonstration of the Lancefield group B carbohydrate antigen, such as with latex agglutination techniques widely used in clinical laboratories. Presumptive identification can be established on the basis of a narrow zone of β-hemolysis on blood agar, resistance to bacitracin and trimethoprim-sulfamethoxazole (TMP-SMX), lack of hydrolysis of bile esculin, and elaboration of CAMP factor (named for the discoverers, Christie, Atkins, and Munch-Petersen), an extracellular protein that, in the presence of the β toxin of Staphylococcus aureus, produces a zone of enhanced hemolysis on sheep blood agar. Individual GBS strains are serologically classified according to the presence of 1 of the structurally distinct capsular polysaccharides, which are important virulence factors and stimulators of antibody-associated immunity. Ten GBS capsular types have been identified: types Ia, Ib, II, III, IV, V, VI, VII, VIII, and IX.

Epidemiology

GBS emerged as a prominent neonatal pathogen in the late 1960s. For the next 2 decades, the incidence of neonatal GBS disease remained fairly constant, affecting 1.0-5.4 per 1,000 liveborn infants in the United States. Two patterns of disease were seen: early-onset disease , which presents at <7 days of age, and late-onset disease , which presents at ≥7 days of age. Since the early 1990s, widespread implementation of maternal intrapartum chemoprophylaxis has led to a striking decrease in the incidence of early-onset neonatal GBS disease in the United States, from 1.7 to 0.25 per 1,000 live births in recent years. This strategy has not had a significant effect on the incidence of late-onset disease, which has remained stable at approximately 0.3-0.4 per 1,000 live births ( Fig. 211.1 ). The incidence of neonatal GBS disease is higher in premature and low-birthweight infants, although most cases occur in full-term infants. Rates of both early- and late-onset disease are higher in black infants.

Colonization by GBS in healthy adults is common. Vaginal or rectal colonization occurs in up to approximately 30% of pregnant women and is the usual source for GBS transmission to newborn infants. In the absence of maternal chemoprophylaxis, approximately 50% of infants born to colonized women acquire GBS colonization, and 1–2% of infants born to colonized mothers develop early-onset disease. Heavy maternal colonization increases the risk for infant colonization and development of early-onset disease. Additional risk factors for early-onset disease include prolonged rupture of membranes, intrapartum fever, prematurity, maternal bacteriuria during pregnancy, or previous delivery of an infant who developed GBS disease. Risk factors for late-onset disease are less well defined. Whereas late-onset disease may follow vertical transmission, horizontal acquisition from nursery or other community sources (family, healthcare providers, placental capsules) has also been described.

GBS is also an important cause of invasive disease in adults. GBS may cause urinary tract infections, bacteremia, endometritis, chorioamnionitis, and wound infection in pregnant and parturient women. In nonpregnant adults, especially those with underlying medical conditions such as diabetes mellitus, cirrhosis, or malignancy, GBS may cause serious infections such as bacteremia, skin and soft tissue infections, bone and joint infections, endocarditis, pneumonia, and meningitis. In the era of maternal chemoprophylaxis, most invasive GBS infections occur in nonpregnant adults. Unlike neonatal disease, the incidence of invasive GBS disease in adults has increased substantially, doubling between 1990 and 2007.

The serotypes most frequently associated with neonatal GBS disease are types Ia, III, and V; Ib and II are less common. Strains of serotype III are isolated in >50% of cases of late-onset disease and of meningitis associated with early- or late-onset disease. The serotype distribution of colonizing and invasive isolates from pregnant women is similar to that from infected newborns. In Japan, serotypes VI and VIII have been reported as common maternal colonizing serotypes, and case reports indicate that type VIII strains may cause neonatal disease indistinguishable from that caused by other serotypes.

Pathogenesis

A major risk factor for the development of early-onset neonatal GBS infection is maternal vaginal or rectal colonization by GBS. Infants acquire GBS by ascending infection or during passage through the birth canal. Fetal aspiration of infected amniotic fluid may occur. The incidence of early-onset GBS infection increases with the duration of rupture of membranes. Infection may also occur through seemingly intact membranes. In cases of late-onset infection, GBS may be vertically transmitted or acquired later from maternal or nonmaternal sources.

Several bacterial factors are implicated in the pathophysiology of invasive GBS disease, primarily the type-specific capsular polysaccharide . Strains that are associated with invasive disease in humans elaborate more capsular polysaccharide than do colonizing isolates. All GBS capsular polysaccharides are high-molecular-weight polymers composed of repeating oligosaccharide subunits that include a short side chain terminating in N -acetylneuraminic acid ( sialic acid ). Studies in type III GBS show that the sialic acid component of the capsular polysaccharide prevents activation of the alternative complement pathway in the absence of type-specific antibody. Sialylated capsular polysaccharide on the GBS surface also interacts with sialic acid–binding lectins or siglecs on human leukocytes to dampen inflammatory gene activation. Thus, the capsular polysaccharide appears to exert a virulence effect by protecting the organism from opsonophagocytosis in the nonimmune host and by downregulating leukocyte activation. In addition, type-specific virulence attributes are suggested by the fact that type III strains are implicated in most cases of late-onset neonatal GBS disease and meningitis. Type III strains are taken up by brain endothelial cells more efficiently in vitro than are strains of other serotypes, although studies using acapsular mutant strains demonstrate that it is not the capsule itself that facilitates cellular invasion. A single clone of type III GBS is highly associated with late-onset disease and meningitis. This clonal group, ST-17, produces a surface-anchored protein called hypervirulent GBS adhesin ( HvgA ) that is not present in other GBS isolates. HvgA contributes to GBS adherence to intestinal and endothelial cells and mediates invasion into the central nervous system (CNS) in an experimental infection model in mice. Other putative GBS virulence factors include GBS surface proteins, which may play a role in adhesion to host cells; C5a peptidase, which is postulated to inhibit the recruitment of polymorphonuclear cells into sites of infection; β-hemolysin, which has been associated with cell injury in vitro; and hyaluronidase, which has been postulated to act as a spreading factor in host tissues.

In a classic study of pregnant women colonized with type III GBS, those who gave birth to healthy infants had higher levels of capsular polysaccharide–specific antibody than those who gave birth to infants who developed invasive disease. In addition, there is a high correlation of antibody titer to GBS type III in mother–infant paired sera. These observations indicate that transplacental transfer of maternal antibody is critically involved in neonatal immunity to GBS. Optimal immunity to GBS also requires an intact complement system. The classical complement pathway is an important component of GBS immunity in the absence of specific antibody; in addition, antibody-mediated opsonophagocytosis may proceed by the alternative complement pathway. These and other results indicate that anticapsular antibody can overcome the prevention of C3 deposition on the bacterial surface by the sialic acid component of the type III capsule.

The precise steps between GBS colonization and invasive disease remain unclear. In vitro studies showing GBS entry into alveolar epithelial cells and pulmonary vasculature endothelial cells suggest that GBS may gain access to the bloodstream by invasion from the alveolar space, perhaps following intrapartum aspiration of infected fluid. β-Hemolysin/cytolysin may facilitate GBS entry into the bloodstream following inoculation into the lungs. However, highly encapsulated GBS strains, which enter eukaryotic cells poorly in vitro compared with capsule-deficient organisms, are associated with virulence clinically and in experimental infection models.

GBS induces the release of proinflammatory cytokines. The group B antigen and the peptidoglycan component of the GBS cell wall are potent inducers of tumor necrosis factor-α release in vitro, whereas purified type III capsular polysaccharide is not. Even though the capsule plays a central role in virulence through avoidance of immune clearance, the capsule does not directly contribute to cytokine release and the resultant inflammatory response.

The complete genome sequences of hundreds of GBS strains have been reported, emphasizing a genomic approach to better understanding GBS. Analysis of these sequences shows that GBS is closely related to Streptococcus pyogenes and Streptococcus pneumoniae. Many known and putative GBS virulence genes are clustered in pathogenicity islands that also contain mobile genetic elements, suggesting that interspecies acquisition of genetic material plays an important role in genetic diversity.