Pathogenesis & Epidemiology

Humans are the only natural hosts for meningococci. The organisms are transmitted by airborne droplets; they colonize the membranes of the nasopharynx and become part of the transient flora of the upper respiratory tract. Carriers are usually asymptomatic. From the nasopharynx, the organism can enter the bloodstream and spread to specific sites, such as the meninges or joints, or be disseminated throughout the body (meningococcemia). About 5% of people become chronic carriers and serve as a source of infection for others. The carriage rate can be as high as 35% in people who live in close quarters (e.g., military recruits); this explains the high frequency of outbreaks of meningitis in the armed forces prior to the use of the vaccine. The carriage rate is also high in close (family) contacts of patients. Outbreaks of meningococcal disease also have occurred in college students living in dormitories.

Two organisms cause more than 80% of cases of bacterial meningitis in infants older than 2 months of age: Streptococcus pneumoniae and N. meningitidis. Of these organisms, meningococci, especially those in group A, are most likely to cause epidemics of meningitis. Group B meningococci cause many cases of meningitis in developed countries because it is not present in the vaccine (see "Prevention", later). Overall, N. meningitidis ranks second to S. pneumoniae as a cause of meningitis but is the most common cause in persons between the ages of 2 and 18 years.

Meningococci have three important virulence factors:

(1) A polysaccharide capsule that enables the organism to resist phagocytosis by polymorphonuclear leukocytes (PMNs).

(2) Endotoxin, which causes fever, shock, and other pathophysiologic changes (in purified form, endotoxin can reproduce many of the clinical manifestations of meningococcemia).

(3) An immunoglobulin A (IgA) protease that helps the bacteria attach to the membranes of the upper respiratory tract by cleaving secretory IgA.

Resistance to disease correlates with the presence of antibody to the capsular polysaccharide. Most carriers develop protective antibody titers within 2 weeks of colonization. Because immunity is group-specific, it is possible to have protective antibodies to one group of organisms yet be susceptible to infection by organisms of the other groups. Complement is an important feature of the host defenses, because people with complement deficiencies, particularly in the late-acting complement components (C6-C9), have an increased incidence of meningococcal bacteremia.

Clinical Findings

The two most important manifestations of disease are meningococcemia (Figure 1) and meningitis. The most severe form of meningococcemia is the life- threatening Waterhouse-Friderichsen syndrome, which is characterized by high fever, shock, widespread purpura, disseminated intravascular coagulation,

thrombocytopenia, and adrenal insufficiency. Bacteremia can result in the seeding of many organs, especially the meninges. The symptoms of meningococcal meningitis are those of a typical bacterial meningitis, namely, fever, headache, stiff neck, and an increased level of PMNs in spinal fluid.

Laboratory Diagnosis

The principal laboratory procedures are smear and culture of blood and spinal fluid samples. A presumptive diagnosis of meningococcal meningitis can be made if gram-negative cocci are seen in a smear of spinal fluid . The organism grows best on chocolate agar incubated at 37°C in a 5% CO2 atmosphere. A presumptive diagnosis of Neisseria can be made if oxidase-positive colonies of gram-negative diplococci are found . The differentiation between N. meningitidis and N. gonorrhoeae is made on the basis of sugar fermentation: meningococci ferment maltose, whereas gonococci do not (both organisms ferment glucose). Immunofluorescence can also be used to identify these species. Tests for serum antibodies are not useful for clinical diagnosis. However, a procedure that can assist in the rapid diagnosis of meningococcal meningitis is the latex agglutination test, which detects capsular polysaccharide in the spinal fluid.

Treatment

Penicillin G is the treatment of choice for meningococcal infections. A third- generation cephalosporin such as ceftriaxone can also be used. Strains resistant to penicillin have rarely emerged, but sulfonamide resistance is common. In 2007- 2008, strains of N. meningitidis resistant to ciprofloxacin emerged.

Prevention

Chemoprophylaxis and immunization are both used to prevent meningococcal disease. Either rifampin or ciprofloxacin can be used for prophylaxis in people who have had close contact with the index case. These drugs are preferred because they are efficiently secreted into the saliva, in contrast to penicillin G.

There are three forms of the meningococcal vaccine for use in the United States, all of which contain the capsular polysaccharide of groups A, C, Y, and W-135 as the immunogen. There are two forms of the conjugate vaccine: Menactra contains the four polysaccharides conjugated to diphtheria toxoid as the carrier protein, whereas Menveo contains the four polysaccharides conjugated to a nontoxic mutant of diphtheria toxin as the carrier protein. Menomune, the unconjugated vaccine, contains only the four polysaccharides (not conjugated to a carrier protein). The conjugate vaccines induce higher titers of antibodies in children than does the unconjugated vaccine. The vaccines induce similar antibody titers in adults. Note that none of the vaccines contain the group B polysaccharide because it is not immunogenic in humans. A fourth vaccine created for use in the meningitis belt of Africa called MenAfrivac is a conjugate vaccine that contains only the group A polysaccharide.

In general, the conjugate vaccines are preferred over the unconjugated version. The unconjugated vaccine is effective in preventing epidemics of meningitis and in reducing the carrier rate, especially in military personnel. Travelers to areas where epidemics are occurring should receive the vaccine. College students living in dormitories are encouraged to receive the vaccine. No booster dose is recommended for either form of the vaccine if given after the age of 16 years. The conjugate vaccine is recommended for children at the age of 11 to 12 years, which will reduce the incidence of meningococcal disease in teenagers and young adults. A booster dose is recommended for those who received the conjugate vaccine prior to the age of 16. Vaccine Adverse Events Reports describe several cases of Guillain-Barré syndrome following immunization with Menactra. A causal relationship between the immunization and Guillain-Barré syndrome has not been established.