Meningococcal Infections

Etiology and microbiology: Neisseria meningitidis is a catalase- and oxidase-positive, gram-negative aerobic diplococcus with a polysaccharide capsule that colonizes humans only.
- - Of the 13 identified serogroups, only 6—A, B, C, X, Y, and W (formerly W135)—account for the majority of cases of invasive disease.
- - Serogroups A, X, and W cause recurrent epidemics in sub-Saharan Africa. Serogroup B can cause hyperendemic disease, and serogroups C and Y cause sporadic disease and small outbreaks.
Epidemiology: Up to 500,000 cases of meningococcal disease occur worldwide each year, with a mortality rate of ~10%.
- - Most commonly, meningococci asymptomatically colonize the nasopharynx; such asymptomatic nasopharyngeal carriage is detected in >25% of healthy adolescents and ~10% of adults.
- - Patterns of meningococcal disease include epidemics, outbreaks (e.g., in colleges, refugee camps), hyperendemic disease, and sporadic or endemic cases.
- - Although most countries have predominantly sporadic cases (0.3-5 cases per 100,000 population), epidemics in sub-Saharan Africa can have rates as high as 1000 cases per 100,000 population.
- - Rates of meningococcal disease are highest among infants, with a second peak in adolescents and young adults (15-25 years of age).
- - Other risk factors for meningococcal disease include complement deficiency (e.g., C5-C9, properdin, factor D), close contact with carriers, exposure to tobacco smoke, and a recent URI caused by a virus or Mycoplasma species.
Pathogenesis: Meningococci colonizing the upper respiratory tract invade the bloodstream through the mucosa only rarely, usually within a few days after an invasive strain is acquired.
- - The capsule is an important virulence factor, providing resistance to phagocytosis and helping prevent desiccation during transmission between hosts.
- - Severity of disease is related to the degree of endotoxemia and the magnitude of the inflammatory response.
- - Endothelial injury leads to increased vascular permeability and hypovolemia, resulting in vasoconstriction and ultimately in decreased cardiac output.
- - Intravascular thrombosis caused by activation of procoagulant pathways and downregulation of anticoagulant pathways results in the characteristic purpura fulminans often seen in meningococcemia.
Clinical manifestations: The most common clinical syndromes are meningitis and meningococcal septicemia, with disease usually developing within 4 days of organism acquisition.
- - A nonblanching rash (petechial or purpuric) develops in >80% of cases; early in the illness, the rash is often absent or may be indistinguishable from viral rashes.
- - Meningococcal meningitis alone (without septicemia) accounts for 30-50% of cases.
  - This meningitis is indistinguishable from other forms of bacterial meningitis unless there is an associated petechial or purpuric rash.
  - Classic signs of meningitis (e.g., headache, neck stiffness, photophobia) are often absent or difficult to discern in infants and young children.
- - Meningococcal septicemia alone accounts for ~20% of cases and initially may present as an influenza-like illness (e.g., fever, headache, myalgias, vomiting, abdominal pain).
  - May progress to shock (e.g., tachycardia, poor peripheral perfusion, oliguria), decreased level of consciousness due to decreased cerebral perfusion, spontaneous hemorrhage (pulmonary, gastric, or cerebral), and ultimately multiorgan failure and death
  - Poor prognostic factors include an absence of meningismus, hypotension, relatively low temperature (<38°C [100.4°F]), leukopenia, and thrombocytopenia.
- - Chronic meningococcemia, which is rarely recognized, presents as repeated episodes of petechial rash associated with fever, joint pain, features of arthritis, and splenomegaly that may progress to acute meningococcal septicemia if untreated.
  - This condition is occasionally associated with complement deficiencies or inadequate sulfonamide therapy.
- - Postmeningococcal reactive disease is immune complex-mediated and occurs 4-10 days after onset of meningococcal disease.
  - Manifestations can include a maculopapular or vasculitic rash (2% of cases), arthritis (≤8% of cases), iritis (1% of cases), or serositis. These features resolve spontaneously without sequelae.
    - - Less common clinical manifestations include pneumonia, pyogenic arthritis, osteomyelitis, purulent pericarditis, endophthalmitis, conjunctivitis, or primary peritonitis.
  - Diagnosis: Although meningococcal infections are often diagnosed on clinical grounds, blood cultures are positive in ~75% of cases and should be performed to confirm the diagnosis and to facilitate public health investigations.
    - - In the setting of fever and petechial rash, elevations in the WBC count and inflammatory marker levels suggest meningococcal disease.
    - - With antibiotic pretreatment, blood cultures are generally negative; in contrast, PCR analysis of whole-blood samples is effective for several days after initiation of antibiotics and increases the diagnostic yield by >40%.
    - - Unless contraindicated on clinical grounds, LP should be performed in cases of suspected meningococcal meningitis.
      - Gram's staining of CSF is ~80% sensitive, and CSF culture is 90% sensitive. Latex agglutination testing of CSF is insensitive and should be avoided.
      - LP should be avoided in pts with meningococcal septicemia, as positioning for the procedure may adversely affect circulatory status.

Treatment: Meningococcal Infections

Initial therapy should focus on urgent clinical issues (e.g., hypovolemic shock, increased intracranial pressure, airway patency) and administration of antibiotics.
Empirical antibiotic therapy for suspected meningococcal disease consists of a third-generation cephalosporin such as ceftriaxone (75-100 mg/kg per day [maximum, 4 g/d] in one or two divided IV doses) or cefotaxime (200 mg/kg per day [maximum, 8 g/d] in four divided IV doses) to provide coverage both for meningococci and for other, potentially penicillin-resistant organisms that may produce an indistinguishable clinical syndrome.
Meningococcal meningitis and meningococcal septicemia are conventionally treated for 7 days.
- - A single dose of ceftriaxone has been used successfully in resource-poor settings.
- - Treatment for meningococcal disease at other foci (e.g., pneumonia, arthritis) is usually continued until clinical and laboratory evidence of infection has resolved; cultures usually become sterile within 24 h of initiation of antibiotics.
Little evidence supports other adjunctive therapies (e.g., antibody to lipopolysaccharide, recombinant bactericidal/permeability-increasing protein, activated protein C) in relevant pt populations; these therapies are not currently recommended.

Prognosis: Despite the availability of antibiotics and other intensive medical interventions, ~10% of pts die.
- - Necrosis of purpuric lesions leads to scarring and the potential need for skin grafting in ~10% of cases.
- - 5% of pts have hearing loss, 7% of pts have neurologic complications, and ~25% of pts with serogroup B meningococcal disease have psychological disorders.
Prevention: Polysaccharide-based and conjugate vaccines exist for primary prevention; secondary cases can be prevented with antibiotic prophylaxis.
- - Meningococcal polysaccharide vaccines are currently formulated as bivalent (serogroups A and C) or quadrivalent (serogroups A, C, Y, and W) and provide adults with immunity of 2-10 years' duration. Because the B polysaccharide is the same as a polysaccharide expressed in fetuses and is therefore recognized as self, serogroup B strains have not been targeted by polysaccharide vaccines.
- - A variety of meningococcal conjugate vaccines have been developed for administration to infants. A quadrivalent formulation (serogroups A, C, Y, and W) is most common in the United States.
- - A combination vaccine that includes outer-membrane vesicles and three recombinant neisserial proteins is effective against serogroup B, is immunogenic in infancy, and has recently been licensed for use.
- - Close contacts (i.e., household and kissing contacts) of pts with meningococcal disease should receive prophylaxis with ciprofloxacin, ofloxacin, or ceftriaxone to eradicate nasopharyngeal colonization by N. meningitidis.
  - Rifampin fails to eradicate carriage in 15-20% of cases, and emerging resistance has been reported.
  - Pts with meningococcal disease who are treated with an antibiotic that does not clear colonization (e.g., penicillin) should also be given a prophylactic agent at the end of therapy.

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