Neisseria meningitidis (Meningococcus)

Etiology

Neisseria meningitidis is a gram-negative, fastidious, encapsulated, oxidase-positive, aerobic diplococcus. Differences in the chemistry of the polysaccharide capsule allow definition of 12 (previously thought to be 13) serologically distinct meningococcal capsular groups, of which 6, designated A, B, C, W (previously designated W135), X, and Y, are responsible for almost all cases of disease. Meningococcal strains may be subclassified on the basis of antigenic variation in 2 porin proteins found in the outer membrane, PorB (serotype) and PorA (serosubtype), and lipopolysaccharide (immunotype), using serology. Serologic typing is being replaced by molecular typing methods, which target genes under immune selection to provide antigen sequence typing (based on amino acid variation in various surface proteins, including PorA and FetA). Sequencing of antigen genes (e.g., PorA, fHbp, NadA, NHBA ) is set to be an important means of monitoring pressure on meningococcal populations by protein-based vaccines. Because meningococci readily exchange genetic material, typing based on a few antigens cannot provide an accurate picture of relatedness of strains, an important goal in monitoring epidemiology. Multilocus sequence typing , which types meningococci using variation in 7 housekeeping genes, has been widely used to map the distribution of genetic lineages of meningococci ( http://pubmlst.org/neisseria/ ) and provides a clearer picture of the genetic and epidemiologic relatedness of strains. To provide still better definition of genetic variation, in some countries, including the United Kingdom, whole genome sequencing is used to type meningococci and appears set to replace both antigen and multilocus sequence typing, as costs continue to fall. The application of molecular approaches to epidemiology has established that (1) endemic meningococcal disease is caused by genetically heterogeneous strains, although only a small number of genetic lineages are associated with the majority of cases of invasive disease; and (2) outbreaks are usually clonal, caused by single strains.

Epidemiology

Meningococci are transmitted during close contact through aerosol droplets or exposure to respiratory secretions, as by kissing. The organism does not survive for long periods in the environment. Enhanced rates of mucosal colonization and increased disease risk are associated with activities that increase the likelihood of exposure to a new strain or increase proximity to a carrier, thus facilitating transmission, including kissing, bar patronage, binge drinking, attendance at nightclubs, men having sex with men, and living in freshman college dormitories. Factors that damage the nasopharyngeal mucosa, such as smoking and respiratory viral infection (notably influenza), are also associated with increased rates of carriage and disease, perhaps by driving upregulation of host adhesion molecules that are receptors for meningococci. Carriage is unusual in early childhood and peaks during adolescence and young adulthood.

Meningococcal disease is a global problem, but disease rates vary by a factor of 10-100–fold in different geographic locations at one point in time and in the same location at different times. Most cases of meningococcal disease are sporadic, but small outbreaks (usually in schools or colleges, representing <3% of U.S. cases), hyperendemic disease (increased rates of disease persisting for a decade or more as a result of a single clone), and epidemic disease are all recognized patterns. However, over the last decade, rates of meningococcal disease have declined in most industrialized countries, partly through introduction of immunization programs, possibly aided by widespread legislation against smoking in public places. The arrival of hyperinvasive lineages and their eventual decline through development of natural immunity is recognized as a major driver of changes in disease rates over time. The U.S. disease rate was 1.1 cases per 100,000 population in 1999 but had fallen to 0.14 per 100,000 by 2014 ( Fig. 218.1 ). By contrast, the rate of disease in Ireland in 1999 was >12 per 100,000, and rates of 1,000 per 100,000 have been described during epidemic disease in sub-Saharan Africa. Disease caused by dominant hyperendemic clones has been recognized in the last decade in Oregon, United States; Quebec, Canada; Normandy, France; and across New Zealand. Laboratory data underreport meningococcal disease incidence rates, because up to 50% of cases are not culture confirmed, particularly where prehospital antibiotics are recommended for suspected cases. In the United Kingdom, polymerase chain reaction (PCR) methods are used routinely for diagnosis of suspected cases, doubling the number of confirmed cases.

The highest rate of meningococcal disease occurs in infants <1 yr old, probably as a result of immunologic inexperience (antibody that recognizes meningococcal antigens is naturally acquired during later childhood), immaturity of the alternative and lectin complement pathways, and perhaps the poor responses made by infants to bacterial polysaccharides. In the absence of immunization, incidence rates decline through childhood, except for a peak of disease among adolescence and young adults, which may be related to increased opportunity for exposure from social activities.

In the United States, most cases of disease in the 1st yr of life are caused by capsular group B strains. After age 1 yr, 85% of disease cases are about equally distributed among capsular groups B and C strains, with the remainder caused by group Y strains. In most other industrialized countries, capsular group B strains predominate at all ages, in part because of introduction of routine capsular group C meningococcal conjugate vaccine among infants and/or toddlers. For reasons not understood, disease in children caused by group Y strains was uncommon in the United States before the 1990s and then began to increase. Rates of disease caused by this capsular group have also increased in several other countries but are declining in the United States. Disease caused by capsular group W strains has increased in the United Kingdom as a result of a hyperinvasive clone, which appears to have originated in Latin America.

Large outbreaks of capsular group A meningococcal disease occurred during and immediately after the First World War and the Second World War in both Europe and the United States, but since the 1990s, almost all cases caused by capsular group A strains have occurred in Eastern Europe, Russia, and developing countries. The highest incidence of capsular group A disease has occurred in a band across sub-Saharan Africa, the meningitis belt , with annual endemic rates of 10-25 per 100,000 population. For more than a century, this region has experienced large capsular group A epidemics every 7-10 yr, with annual rates as high as 1,000 per 100,000 population. The onset of cases in the sub-Saharan region typically begins during the dry season, possibly related to drying and damage to the nasopharyngeal mucosa; subsides with the rainy season; and may reemerge the following dry season. Rates of capsular group A meningococcal disease are currently falling across this region as a result of a mass vaccine implementation targeting strains bearing the A polysaccharide. However, both endemic and epidemic meningococcal disease in this region is also caused by capsular groups C, W, and X strains. Capsular group A and group X are infrequent causes of disease in other areas of the world, although both A and W strains have been associated with outbreaks among pilgrims returning from the Hajj.

Pathogenesis and Pathophysiology

Colonization of the nasopharynx by N. meningitidis is the first step in either carriage or invasive disease. Disease usually occurs 1-14 days after acquisition of the pathogen. Initial contact of meningococci with host epithelial cells is mediated by pili, which may interact with the host CD46 molecule or an integrin. Close adhesion is then mediated by Opa and Opc binding to carcinoembryonic antigen (CEA) cell adhesion molecule receptors and integrins, respectively. Subsequent internalization of meningococci by epithelial cells is followed by transcytosis through to the basolateral tissues and dissemination into the bloodstream. Immunoglobulin A ₁ protease secreted by invasive bacteria degrades secretory IgA on the mucosal surface, circumventing this first-line host defense mechanism.

Once in the bloodstream, meningococci multiply rapidly to high levels to cause septicemia ( meningococcemia ). Patients with a higher bacterial load have a more rapid clinical deterioration and longer period of hospitalization, as well as a higher risk of death and permanent sequelae. Resistance to complement-mediated lysis and phagocytosis is largely mediated by the polysaccharide capsule and lipopolysaccharide (LPS) . Outer membrane vesicles released from the surface of the organism contain LPS, outer membrane proteins, periplasmic proteins, and phospholipid, and play a major role in the inflammatory cascade that leads to severe disease.

Much of the tissue damage is caused by host immune mechanisms activated by meningococcal components, in particular LPS. During invasive disease LPS is bound to a circulating plasma protein, known as LPS-binding protein. The host receptor complex for LPS consists of Toll-like receptor (TLR)-4, CD14, and myeloid differentiation protein 2. Binding of LPS to TLR-4, which is upregulated on circulating leukocytes during septicemia, results in activation of a number of different cell types. An intense inflammatory reaction results from secretion of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor, levels of which are closely associated with plasma levels of LPS. The major antiinflammatory cytokines IL-1Rα, IL-2, IL-4, and IL-12 and transforming growth factor-β are present at very low levels. Both high and low levels have been observed for IL-10 and interferon-γ.

The pathophysiologic events that occur during meningococcal septicemia are largely related to microvascular injury. This leads to increased vascular permeability and the capillary leak syndrome, pathologic vasoconstriction and vasodilation, disseminated intravascular coagulation (DIC), and profound myocardial dysfunction. Increased vascular permeability can lead to dramatic fluid loss and severe hypovolemia. Capillary leak syndrome with or without aggressive fluid resuscitation (which is essential in severe cases) leads to pulmonary edema and respiratory failure. Initial vasoconstriction is a compensatory mechanism in response to hypovolemia and results in the clinical features of pallor and cold extremities. Following resuscitation, some patients experience warm shock , that is, intense vasodilation with bounding pulses and warm extremities, despite persistent hypotension and metabolic acidosis. Virtually all antithrombotic mechanisms appear to be dysfunctional during meningococcal sepsis, leading to a procoagulant state and DIC. All these factors contribute to depressed myocardial function, but there is also a direct negative cytokine effect on myocardial contractility, thought to be largely mediated by IL-6. Hypoxia, acidosis, hypoglycemia, hypokalemia, hypocalcemia, and hypophosphatemia are all common features in severe septicemia and further depress cardiac function. Some patients become unresponsive to the positive inotropic effects of catecholamines and require high levels of inotropic support during intensive care management. These processes result in impairment of microvascular blood flow throughout the body and ultimately lead to multiorgan failure , which is responsible for much of the mortality.

Following invasion of the circulation, meningococci may also penetrate the blood-brain barrier and enter the cerebrospinal fluid (CSF), facilitated by pili and possibly Opc. Once there, bacteria continue to proliferate and LPS and other outer membrane products can stimulate a proinflammatory cascade similar to that observed in the blood. This leads to upregulation of specific adhesion molecules and recruitment of leukocytes into the CSF. Central nervous system damage occurs directly by meningeal inflammation and indirectly by circulatory collapse and causes a high rate of neurologic sequelae in affected patients. Death can occur from cerebral edema, which leads to increased intracranial pressure (ICP) and cerebral or cerebellar herniation.