Probable case: A probable case of meningococcal disease is defined by detection of N. meningitidis DNA by polymerase chain reaction or polysaccharide antigen in CSF (e.g., by latex agglutination or immunohistochemistry), or the presence of clinical purpura fulminans in the absence of diagnostic culture from a person with clinically compatible disease.

Primary case: A primary case of meningococcal disease is one that occurs in the absence of previous known close contact with another patient with meningococcal disease.

Secondary case: A secondary case of meningococcal disease is one that occurs among close contacts of a primary case-patient 24 hours or more after onset of illness in the primary patient.

Co-primary case: Co-primary cases are two or more cases that occur among a group of close contacts with onset of illness separated by less than 24 hours.

Close contacts: Close contacts of a patient who has meningococcal disease include

1. household members (including dormitory room, barracks),
2. child care center contacts, and
3. persons directly exposed to the patient’s oral secretions (e.g., by kissing, mouth-to-mouth resuscitation, endotracheal intubation, or endotracheal tube management).1

Laboratory Testing

N. meningitidis is a gram-negative, encapsulated, aerobic diplococcus. Thirteen different meningococcal serologic groups have been defined, five of which cause the great majority of disease (A, B, C, Y, and W135). The distinction between serogroups is based on the immunochemistry of the capsular polysaccharide, but more recently PCR of capsule biosynthesis genes has been used for determining the serogroup of isolates.19 Serogroup A, C, Y and W135 polysaccharides all elicit a serogroup-specific immune response, which allows for a successful tetravalent vaccine. The serogroup B capsular polysaccharide is poorly immunogenic, thus making it challenging to develop a vaccine to protect against this serogroup. Vaccine development efforts for serogroup B are focusing on outer membrane proteins (OMPs) or other surface molecules rather than the capsular polysaccharide.5

Identification of N. meningitidis

The case definition for confirmed meningococcal disease requires isolation of N. meningitidis from a normally sterile site. Typically, the isolate comes from blood or CSF, but it can also be from joint, pleural, or pericardial fluid. Aspirates or skin biopsies of purpura or petechiae can yield meningococci in cases of meningococcemia. The typical medium used to grow the organism is chocolate agar or Mueller-Hinton medium in an atmosphere containing 5% carbon dioxide.20 Gram staining is commonly used for identification of N. meningitidis and continues to be a reliable and rapid method for presumptive identification. Intracellular gram-negative diplococci in CSF can be considered meningococci until proven otherwise.

In addition to bacteriology for definitive detection and identification, latex agglutination can be used for rapid detection of meningococcal capsular polysaccharides in CSF, although false-negative and false-positive results can occur. Antigen agglutination tests on serum or urine samples are unreliable for diagnosis of meningococcal disease.4

Real-time PCR detects DNA of meningococci in blood, CSF, or other clinical specimens. A major advantage of PCR is that it allows for detection of N. meningitidis from clinical samples in which the organism could not be detected by culture methods, such as when a patient has been treated with antibiotics before obtaining a clinical specimen for culture. Even when the organisms are nonviable following antimicrobial treatment, PCR can still detect N. meningitidis DNA.19 Because of the severity of meningococcal disease, it is critical to treat the patient as soon as infection is suspected, and not to delay to obtain culture or laboratory results first.

Susceptibility testing

Routine antimicrobial susceptibility testing of meningococcal isolates is not currently recommended. N. meningitidis strains with decreased susceptibility to penicillin G have been identified sporadically from several regions of the United States, Europe and Africa.21 Most of these isolates remain moderately susceptible (penicillin minimum inhibitory concentration of 0.12 µg/mL–1.0 µg/mL). High-dose penicillin G remains an effective treatment strategy against moderately susceptible meningococci. Surveillance of susceptibility patterns in populations should be conducted in order to monitor trends in N. meningitidis susceptibility.

Public health impact

Rapid and reliable results are crucial in determining the meningococcal serogroup in an outbreak because public health response will differ for vaccine-preventable or non–vaccine-preventable disease. Outbreaks of meningococcal disease are usually caused by the same or closely related strains.1 Molecular genotyping techniques such as pulsed-field gel electrophoresis, 16S rRNA gene sequencing, or multilocus sequence typing are used for subtype characterization of an outbreak clone.22, 23 This subtyping helps to better define the extent of the outbreak but is not necessary for determining response during the outbreak.

Reporting

Cases of meningococcal disease should be promptly reported to the appropriate local or state health department. Case information should be reported to CDC through the NationalNotifiable Diseases Surveillance System (NNDSS), through the National Electronic Telecommunications System for Surveillance (NETSS), or the National Electronic Disease Surveillance System (NEDSS) within 14 days of the initial report to the state or local health department (see Appendix 9).

Vaccination

A tetravalent meningococcal conjugate vaccine, MCV4 (Menactra®, manufactured by sanofi pasteur) was licensed in January 2005 for persons aged 11–55 years. The Advisory Committee on Immunization Practices (ACIP) recommends MCV4 at age 11–12 years. For those who have not previously received MCV4, ACIP recommends vaccination before high school entry (at approximately 15 years).1 Routine vaccination is also recommended for college freshman living in dormitories and for other populations at increased risk, including

• microbiologists who are routinely exposed to isolates of N. meningitidis
• military recruits
• persons who travel to or reside in countries in which meningococcal disease is hyperendemic or epidemic, particularly if contact with the local population will be prolonged
• persons who have terminal complement component deficiencies
• persons who have anatomic or functional asplenia

Polysaccharide vaccine

The tetravalent meningococcal polysaccharide vaccine, MPSV4 (Menomune-A/C/Y/W135®, manufactured by sanofi pasteur) has been available since the 1970s. Meningococcal polysaccharide vaccines have been used extensively in mass vaccination programs, among international travelers, and in the military.1 Usefulness of the polysaccharide vaccine is limited because it does not confer long-lasting immunity and does not cause a sustainable reduction of nasopharyngeal carriage of N. meningitidis, and therefore does not interrupt transmission sufficiently to elicit herd immunity.1

Conjugate vaccine

The characteristics of conjugate vaccines offer a number of improvements over polysaccharide vaccines. Examples of the successful implementation of conjugate vaccines can be seen in the reduction of Haemophilus influenzae serotype b disease in children younger than 5 years old in the United States3 and in the dramatic reduction in invasive disease caused by Streptococcus pneumoniae.2

Bacterial polysaccharides are T-cell–independent antigens and do not stimulate a memory response. Polysaccharides alone do not confer long-lasting immunity or cause a substantial reduction in nasopharyngeal carriage of N. meningitidis, limiting the ability of polysaccharide vaccine to elicit herd immunity. Conjugating polysaccharide to a protein carrier that contains T-cell epitopes creates a T-cell–dependent immune response. This results in a strong anamnestic response at re-exposure, a substantial primary response in infants, and possibly in reduction in the frequency of N. meningitidis carriage, protecting unvaccinated persons through herd immunity.1

MCV4 was demonstrated to be non-inferior to MPSV4 and was licensed based on safety and immunogenicity data. A randomized controlled trial compared the immunogenicity of MCV4 with that of MPSV4 among 11–18-year-olds, and an additional randomized, controlled trial compared immunogenicity between MCV4 and MPSV4 among 18–55-year-olds.1 Persistence of antibodies after 3 years and response to revaccination were evaluated for MCV4.1 Studies to evaluate the effectiveness of the vaccine, including its effect on carriage, are currently under way.

In October 2005, reports indicating a possible association between Guillain-Barré syndrome (GBS) and receipt of MCV4 were made to the Vaccine Adverse Event Reporting System (VAERS). As of October 2006, a total of 17 cases have been reported in persons receiving Menactra. Preliminary analysis of the data suggests a small association between GBS and MCV4 vaccination, but the inherent limitations of VAERS and the uncertainty of background rates for GBS require that these findings be viewed with caution. Because of the risk of meningococcal disease and the associated morbidity and mortality, CDC continues to recommend routine vaccination with MCV4 for adolescents, college freshman living in dormitories, and other populations at increased risk. Persons with a history of GBS may be at increased risk for GBS and should discuss their risk of meningococcal disease with their healthcare provider when deciding whether to be vaccinated.24

Enhancing Surveillance

CDC coordinates active, population- and laboratory-based surveillance for invasive meningococcal disease as part of the Active Bacterial Core surveillance (ABCs) system, through the Emerging Infections Program (EIP). ABCs comprises 10 sites which collect data from all patients from whom N. meningitidis was isolated from a normally sterile body site. This surveillance program allows for detection of patterns in causative meningococcal serogroups and accurate estimation of age-specific incidence rates.1 ABCs data have been used to track meningococcal disease trends, including the emergence of serogroup Y meningococcal disease. ABCs website is at http://www.cdc.gov/ncidod/dbmd/abcs

In addition, many states have their own enhanced surveillance system for meningococcal disease.

Case Investigation

All reports of suspected meningococcal disease should be investigated immediately. CDC is available to assist with epidemiologic and laboratory investigations during outbreaks. A critical component of case investigation is ensuring that all close contacts (see definitions) receive appropriate chemoprophylaxis to eradicate nasopharyngeal carriage of meningococci and prevent secondary disease. Approximately 70% of secondary cases occur within 7 days of disease onset in the index patient. Antibiotic administration within 24 hours of identifying a case is ideal; after 14 days it is unlikely that antibiotic chemoprophylaxis is helpful.1 Rifampin, ciprofloxacin, and ceftriaxone are all effective as chemoprophylaxis against meningococcal disease.1

Outbreaks

Compared with the 1980s, outbreaks of meningococcal disease have been detected more frequently in the United States. From July 1994 to June 2002, 69 outbreaks were identified. These outbreaks occurred in 30 states and involved 229 cases, accounting for less than 2% of total meningococcal disease cases in the United States during this period. Twenty-five of the 69 outbreaks were community based and 44 were organization based. Of the organization-based outbreaks, 19 occurred in primary and secondary schools, 12 in colleges and universities and 8 in nursing homes. Vaccination campaigns were conducted in 31 outbreaks. Forty-three of the outbreaks were caused by serogroup C, 17 by serogroup B, and 9 by serogroup Y.25

Attack rates

Attack rates are calculated to determine the risk for disease among the general population and to determine whether overall rates have increased. Related cases, defined as secondary and co-primary, should not be included in the calculation of the attack rate. To calculate a primary attack rate all confirmed cases of the same serogroup should be summed, secondary cases should be excluded, and each set of co-primary cases should be counted as one case.

To calculate an attack rate:

Community and organization outbreaks

A community-based outbreak is defined as the occurrence of three or more confirmed or probable primary cases of meningococcal disease in a period of 3 months or less among persons residing in the same area who are not close contacts and who do not share a common affiliation, with a primary attack rate of 10 or more cases per 100,000 population.1 Examples of a community-based outbreak include a neighborhood, town or county.

An organization-based outbreak is defined as the occurrence of three or more confirmed or probable cases of meningococcal disease of the same serogroup in period of 3 months or less among persons who have a common affiliation but no close contact with each other, resulting in a primary disease attack rate of 10 or more cases per 100,000 persons.1 In some instances the attack rate will be greater than 10 cases per 100,000 population with only two or three cases.1 In these situations, vaccination may be considered after only two primary cases are identified. Examples of an organization-based outbreak include cases in schools, churches, and universities.

Population at risk

A population at risk comprises persons who are considered to be at increased risk for meningococcal disease compared with historical rates of disease in the same group of the general U.S. population. Population at risk is usually defined on the basis of community of residence or organizational affiliation. The population at risk is used as the denominator in calculations of the disease attack rate. In organization-based outbreaks the population at risk can be defined as the group of persons that best represent the affiliation. In community-based outbreaks, patients do not share any common affiliation besides an area of residence.1

Decision to vaccinate

When deciding to implement a mass vaccination campaign to prevent meningococcal disease, one must consider whether the cases represent an outbreak or an unusual clustering of endemic cases. Mass vaccination programs are expensive, require considerable public health effort, and may create excessive concern among the public. Because the number of cases in outbreaks is usually not substantial, this determination requires evaluation and analysis of the patterns of disease occurrence.13

Vaccination of the population at risk should be considered if the attack rate is greater than 10 cases per 100,000 population, but the actual attack rate at which the decision to vaccinate is made will vary. The following factors should be considered when making the decision to vaccinate:

• Completeness of case reporting and number of possible cases of meningococcal disease for which bacteriologic confirmation or serogroup data are not available
• Occurrence of additional cases of meningococcal disease after recognition of a suspected outbreak (e.g., if the outbreak occurred 2 months previously and no additional case have occurred, vaccination might be unlikely to prevent additional cases of meningococcal disease)
• Logistic and financial considerations

Current meningococcal vaccines are not effective against N. meningitidis serogroup B; therefore, vaccination should not be considered during a serogroup B outbreak.

Other control measures

Mass chemoprophylaxis is not recommended for control of large outbreaks of disease for multiple reasons: cost of drug and administration, difficulty of ensuring simultaneous administration of drugs to substantial populations, drug side effects, and emergence of resistant organisms. In most outbreak settings, these disadvantages outweigh the potential benefit. Situations in which mass chemoprophylaxis could be successful include those involving limited or closed populations, such as a single school or residential facility. This is especially important in serogroup B outbreaks, since vaccines cannot be used for control and prevention. If the decision is made to use mass chemoprophylaxis, it should be administered to all persons at the same time.1

It is possible that even in a vaccine-preventable, organization-based outbreak, antibiotic distribution may be a more timely intervention, since preventive antibodies take 7–10 days to develop after vaccination.1 Again, the potential benefit of mass chemoprophylaxis must be weighed against the possible emergence of antibiotic resistance and the logistics of launching a prophylaxis campaign.

Restricting travel to areas with an outbreak, closing schools or universities, or cancelling sporting or social events are not recommended measures for outbreak control in the United States. A crucial part of managing suspected meningococcal disease outbreaks and promoting early case recognition is educating communities, physicians and other healthcare workers about meningococcal disease.1

References

1. CDC. Prevention and control of meningococcal disease. MMWR 2005;54(No. RR-7):1–17.
2. Whitney CG, Farley MM, Hadler J, Harrison LH, Bennett NM, Lynfield R, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003;348:1737–46.
3. Schuchat A, Robinson K, Wenger JD, Harrison LH, Farley M, Reingold AL, et al. Bacterial meningitis in the United States in 1995. N Engl J Med 1997;337:970–6.
4. Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JM. Meningococcal disease. N Engl J Med 2001;344:1378–88.
5. Raghunathan PL, Bernhardt SA, Rosenstein NE. Opportunities for control of meningococcal disease in the United States. Annu Rev Med 2004;55:333–53.
6. Fischer M, Hedberg K, Cardosi P, Plikaytis B, Hoesly FC, Steingart K, et al. Tobacco smoke as a risk factor for meningococcal disease. Pediatr Infect Dis J 1997;16:979–83.
7. Harrison LH, Dwyer DM, Maples CT, Billman L. Risk of meningococcal infection in college students. JAMA 1999;281:1906–10.
8. Rosenstein NE, Perkins BA, Stephens DS, Lefkowitz L, Cartter ML, Danila R, et al. The changing epidemiology of meningococcal disease in the United States, 1992–1996. J Infect Dis 1999;180:1894–901.
9. Shepard CW, Rosenstein NE, Fischer M, Active Bacterial Core Surveillance Team. Neonatal meningococcal disease in the United States, 1990 to 1999. Pediatr Infect Dis J 2003;22:418–22.
10. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med 1969;129:1307–26.
11. Munford RS, Taunay Ade E, de Morais JS, Fraser DW, Feldman RA. Spread of meningococcal infection within households. Lancet 1974;1:1275–8.
12. De Wals P, Hertoghe L, Borlee-Grimee I, De Maeyer-Cleempoel S, Reginster-Haneuse G, Dachy A, et al. Meningococcal disease in Belgium. Secondary attack rate among household, day-care nursery and pre-elementary school contacts. J Infect 1981;3(1 Suppl):53–61.
13. Zangwill KM, Schuchat AS, Riedo FX, Pinner RW, Koo DT, Reeves MW, et al. School-based clusters of meningococcal disease in the United States. JAMA 1997;277:389–95.
14. Artenstein MS, Rust JH, Hunter DH, Lamson TH, Buescher EL. Acute respiratory disease and meningococcal infection in army recruits. JAMA 1967;201:1004–7.
15. Kirsch EA, Barton RP, Kitchen L, Giroir BP. Pathophysiology, treatment and outcome of meningococcemia: a review and recent experience. Pediatr Infect Dis J 1996;15:967–79.
16. Council of State and Territorial Epidemiologists. Position Statement 14-ID-08, Meningococcal serogroup surveillance. CSTE 2004. Available at: http://www.cste.org/ps/2004pdf/04-ID-08-final.pdf (exit site)
17. U.S. Department of Health and Human Services. Healthy People 2010. 2nd. ed. With understanding and improving health and objectives for improving health (2 vols.). Washington DC: US Department of Health and Human Services, 2000.
18. CDC. Active Bacterial Core Surveillance Report, Emerging Infections Program Network. Neisseria meningitidis, 2005. 2006. Available at: http://www.cdc.gov/ncidod/dbmd/abcs/survreports.htm
19. Mothershed EA, Sacchi CT, Whitney AM, Barnett GA, Ajello GW, Schmink S, et al. Use of real-time PCR to resolve slide agglutination discrepancies in serogroup identification of Neisseria meningitidis. J Clin Microbiol 2004;42:320–8.
20. Granoff DM, Feavers IM, Borrow R. Meningococcal vaccines. In: Plotkin SA, Orenstein WA, Offit PA. Vaccines. 4th ed. Philadelphia: Saunders; 2003:959–87.
21. American Academy of Pediatrics. Meningococcal infections. In: Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Red Book: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006:452–60.
22. Sacchi, CT, Whitney AM, Reeves MW, Mayer LW, Popovic T. Sequence diversity of Neisseria meningitidis 16S rRNA genes and use of 16S rRNA gene sequencing as a molecular subtyping tool. J Clin Microbiol 2002;40:4520–7.
23. Maiden, MC, Bygraves JA, Feil E, Morelli G, Russell JE, Urwin R, et al. Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms. Proc Natl Acad Sci USA 1998;95:3140–5.
24. CDC. Update: Guillain-Barré syndrome among recipients of Menactra® meningococcal conjugate vaccine—United States, June 2005–September 2006. MMWR 2006;55(41):1120–4.
25. Brooks R, Woods CW, Benjamin DK, Rosenstein NE. Increased case-fatality rate associated with outbreaks of Neisseria meningitidis infection, compared with sporadic meningococcal disease, in the United States, 1994–2002. Clin Infect Dis 2006;43:49–54.

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