Infections Caused by Neisseria meningitidis

Acknowledgment

The author acknowledges Anjali N. Kunz for contributions to the previous edition.

Abstract

Neisseria meningitidis is both a commensal organism of the upper respiratory tract and a significant pathogen for humans. It causes devastating disease with significant morbidity and mortality worldwide. Infections caused by N. meningitidis can have various clinical presentations ranging from asymptomatic carriage or a mild upper respiratory illness to purulent meningitis and/or disseminated disease with fulminant sepsis. Strains with capsule types belonging to groups A, B, C, Y, W, and recently X are associated with invasive disease. The majority of patients infected with N. meningitidis are children, usually younger than 5 years old, adolescents, young adults, and adults older than 65 years of age. Effective polysaccharide and polysaccharide conjugate vaccines are available for prevention of serogroup A, C, Y, and W disease. The serogroup B polysaccharide is poorly immunogenic, and outer membrane protein–based vaccines have been developed and recently licensed.

Clinical Vignette

A 17-year-old previously healthy female university student was brought to the emergency room with symptoms of fever, headache, and malaise. She had been well until the prior evening, when her symptoms began with generalized fatigue causing her to leave her friends early to go to sleep in her dormitory. She felt too ill to join them for breakfast, and when they returned to her room they were concerned to find her confused and febrile.

Her exam was significant for a temperature of 102°F, photophobia, and positive Kernig and Brudzinski signs (pain with hip flexion and knee extension, and flexion of the hips and knees when the neck is flexed by the examiner, respectively). Rare, fine petechiae were present on her trunk and upper extremities, and the rash progressed during the evaluation. Laboratory investigations revealed a total leukocyte count of 19000/mm ³ and a platelet count of 10000/mm ³ . Blood cultures and lumbar puncture were performed. Cerebrospinal fluid (CSF) white blood cell (WBC) count was 15 with 80% neutrophils. Gram stain revealed gram-negative diplococci.

The patient was initially treated with vancomycin (1 g intravenously every 12 hours) and ceftriaxone (1 g intravenously every 12 hours). The patient showed early signs of hemodynamic instability (systolic blood pressure of 80 mm Hg and heart rate of 140/min) in spite of an initial intravenous fluid bolus, and she was transferred to the intensive care unit for continued fluid and inotropic support. Norepinephrine was required at a rate of 1 mcg/kg/min during the first 8 hours of admission but was successfully discontinued during the first hospital day. Dexamethasone was administered for the first 4 days because the CSF gram stain and subsequent culture confirmed Neisseria meningitidis meningitis in addition to sepsis. Vancomycin was stopped following culture confirmation of N. meningitidis .

COMMENT: The patient recovered rapidly and continued antibiotics for 7 days. Close monitoring for sequelae of meningitis including hearing loss and cognitive dysfunction was planned. Antibiotic prophylaxis was administered to her roommates and boyfriend.

Geographic Distribution and Burden Of Disease

N. meningitidis has a worldwide distribution, but there are distinct regional characteristics of the microbiology and epidemiology of disease. The Centers for Disease Control and Prevention (CDC) has reported the worldwide incidence of invasive meningococcal disease to be 0.5 to 5 per 100,000 population per year. In the United States the overall incidence ranged from 0.5 to 1.5 per 100,000 population per year in the 1990s but has declined over the past two decades to 0.11 cases per 100,000 persons in 2017. Disease is primarily caused by serogroup B, although cases of C, Y, and W occur. European countries have a wide range of disease incidence (0.2 to 14 cases per 100,000). The majority of these cases are caused by serogroup B, especially in countries where meningococcal C conjugate (MCC) vaccines are used routinely. An epidemic of serogroup B meningococcal disease persisted for almost a decade in New Zealand (17.4 cases per 100,000 in 2001), but attack rates declined to 2.6 per 10,000 in 2007, at least in part as a result of a national vaccination campaign using an outer membrane vesicle (OMV) vaccine made from the outbreak strain.

Before World War II, serogroup A was the most common serogroup identified from disease isolates in industrialized countries. In the second half of the 20th century, this serogroup was primarily associated with epidemic meningitis, especially in the sub-Saharan region of Africa known as the meningitis belt. Countries in this region experienced recurrent epidemics every 5 to 10 years with incidence rates reaching 1000 per 100,000. Even in interepidemic years, serogroup A disease rates were as high as 25 per 100,000. Following introduction and widespread use of a serogroup A meningococcal conjugate vaccine (MenAfriVac) in national vaccination campaigns, serogroup A epidemics have disappeared from this region. Serogroup A epidemics also occurred in India, China, and Russia. Other areas of Africa have yearly rates of invasive serogroup A disease higher than in industrialized nations. Travel to the Hajj pilgrimage has been a significant risk factor for exposure to serogroup A meningococci.

Asymptomatic nasopharyngeal carriage of N. meningitidis is common and varies by age. Infants have a carriage rate of 1% to 2%, whereas adolescents and young adults have a carriage rate of 15% to 25%. Carriage of highly virulent strains occurs in less than 5% of the general population, even during outbreaks. Carriage isolates are often unencapsulated, or less virulent, than strains that cause invasive disease. Transmission of N. meningitidis is primarily through respiratory droplets. Invasive meningococcal disease is associated with recent acquisition of a new pathogenic strain rather than after extended colonization. Studies of military recruits in the 1970s helped to determine the infectivity and route of spread of the organism and established that preexisting antibodies that trigger complement-mediated killing of the bacteria provide protection against invasive disease.

The prevalence of bactericidal antibodies in the population increases with age and is inversely related to the rates of invasive disease. Infection rates are highest in children younger than age 5 years, especially 6 months to 1 year of age. A second period of increased risk is observed during adolescence and young adulthood. College freshman living in dormitories and military recruits are at moderate risk, whereas and individuals with close or intimate contact with an index case are at 500 times increased risk of invasive disease. Individuals with terminal complement component deficiencies or those who are receiving complement inhibitor therapies are at high risk of recurrent invasive meningococcal infections.

Pathogenesis

N. meningitidis, a gram-negative diplococcus, is an obligate human pathogen. Endemic sporadic disease is caused by highly diverse strains, but most disease isolates can be grouped by genetic analysis of housekeeping genes (multilocus sequence typing [MLST]) into one of several hypervirulent lineages. In contrast, local outbreaks and sustained epidemics can be caused by a single strain type and are considered clonal.

Surface structures of the bacterium are important for strain characterization, disease pathogenesis, and immunity. Capsular polysaccharide type defines the serogroup of a strain. Strains expressing serogroup A, B, C, Y, W, and more recently serogroup X capsules are associated with invasive disease, whereas unencapsulated strains and strains of the remaining serogroups are usually associated with asymptomatic nasopharyngeal colonization. The polysaccharide capsule enhances efficient transmission and inhibits phagocytosis. Lipooligosaccharide (LOS) is an endotoxin that induces an inflammatory cascade that leads to the clinical features seen in septicemia, septic shock, and meningitis.

N. meningitidis has extensive mechanisms for the uptake and incorporation of deoxyribonucleic acid (DNA), a process known as horizontal exchange, which allows the organism to adapt to the host and evade natural immunity. This process results in antigenic diversity of many surface proteins and occasionally capsule type switching. In addition, phase variation of surface structures such as Opa proteins and LOS also contribute to phenotypic diversity of the organism.

Genetic polymorphisms of the human host affect susceptibility to meningococcal infections and may affect disease outcomes. Genetic deficiencies of complement factors 5 to 9 (late complement component deficiency) are well recognized risk factors for recurrent or familial meningococcal disease. In addition, some case control studies have shown an association between meningococcal disease and polymorphisms of interleukin-1 receptor agonist (IL1RA), carcinoembryonic antigen cell adhesion molecules 3 and 6, surfactant proteins A and D, and factor H.

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