Meningococcal Infection

1. Introduction

Meningococcal disease, caused by Neisseria meningitidis, remains a significant public health challenge globally. It manifests as a spectrum of illnesses ranging from asymptomatic carriage to invasive diseases like meningitis and fulminant septicemia (meningococcemia). Despite advances in critical care, the case fatality rate remains high (5–10%), and survivors often suffer severe sequelae such as hearing loss, neurologic disability, or limb loss. It is the leading cause of bacterial meningitis in older children and adolescents in developed nations following the introduction of Haemophilus influenzae type b (Hib) and pneumococcal conjugate vaccines.

2. Etiology and Microbiology

2.1. The Organism

• Classification: N. meningitidis is a Gram-negative, aerobic (facultatively anaerobic), oxidase-positive, and catalase-positive diplococcus.
• Morphology: It typically appears as kidney-bean-shaped pairs with flattened adjacent sides. It is non-motile and non-spore-forming.
• Culture Characteristics: It is a fastidious organism requiring enriched media like chocolate agar or blood agar and an atmosphere of 3–5% $C{O}_2$ for optimal growth. It oxidizes glucose and maltose (differentiating it from N. gonorrhoeae, which oxidizes only glucose).

2.2. Serogroups and Typing

Classification is crucial for epidemiology and vaccine formulation:

1. Serogroups: Based on the chemical composition of the polysaccharide capsule. There are 12 serogroups, but six cause almost all invasive disease: A, B, C, W, X, and Y.
   • Serogroup A: Historically associated with massive epidemics in the sub-Saharan "meningitis belt".
   • Serogroups B and C: Major causes of endemic disease in industrialized nations.
   • Serogroup W: Associated with outbreaks among Hajj pilgrims.
2. Serotypes and Serosubtypes: Based on outer membrane proteins PorB and PorA, respectively.
3. Molecular Typing: Multilocus sequence typing (MLST) is now the gold standard for defining genetic lineages.

2.3. Virulence Factors

• Polysaccharide Capsule: The primary virulence factor, inhibiting phagocytosis and complement-mediated lysis.
• Endotoxin (Lipooligosaccharide - LOS): A potent inducer of the inflammatory cytokine storm (TNF-$\alpha$, IL-1, IL-6), leading to septic shock, capillary leak, and coagulopathy.
• Pili and Adhesins (Opa, Opc): Mediate attachment to nasopharyngeal epithelial cells.
• IgA1 Protease: Cleaves secretory IgA, facilitating mucosal colonization.

3. Epidemiology

3.1. Transmission and Carriage

• Reservoir: The human nasopharynx is the only natural reservoir. Transmission occurs via direct contact with respiratory secretions (droplets) or saliva (e.g., kissing).
• Carriage: Asymptomatic carriage is common (approx. 10% overall). Rates are low in young children (~2%) but peak in adolescents and young adults (up to 25–30%), who serve as the primary reservoir for transmission.
• Risk Factors for Transmission: Crowding (military recruits, college dormitories, Hajj pilgrimage), active and passive smoking, and concurrent viral respiratory infections (e.g., influenza).

3.2. Host Susceptibility

• Age: The highest incidence is in infants <1 year (waning maternal antibody), with a second peak in adolescents (15–19 years).
• Immunity: Protection correlates with serum bactericidal antibody (SBA) levels.
• High-Risk Groups:
  • Complement Deficiency: Terminal complement pathway defects (C5–C9) or properdin deficiency increase risk by up to 600-fold, often with unusual serogroups (Y, W, X).
  • Asplenia: Functional or anatomic asplenia.
  • Medications: Use of eculizumab (terminal complement inhibitor).
  • HIV Infection: Increased incidence of invasive disease.

4. Pathogenesis

1. Colonization: Bacteria attach to the non-ciliated columnar epithelium of the nasopharynx via pili and outer membrane proteins.
2. Invasion: Bacteria penetrate the mucosa via transcytosis and enter the bloodstream.
3. Survival: The capsule protects against host lysis. In susceptible hosts (lacking specific SBA), rapid multiplication occurs.
4. Inflammatory Cascade:
   • Release of outer membrane vesicles containing LOS triggers a massive release of cytokines (TNF-$\alpha$, IL-1, IL-6).
   • This leads to endothelial injury, increased vascular permeability (capillary leak), pathological vasoconstriction/vasodilation, and profound myocardial dysfunction.
   • Coagulopathy: Endothelial damage and procoagulant activation lead to disseminated intravascular coagulation (DIC), thrombosis of small vessels, and purpura fulminans.
5. CNS Invasion: Bacteria traverse the blood-brain barrier via interaction with cerebral endothelial cells, causing purulent meningitis.

5. Clinical Manifestations

The incubation period is 1–14 days, typically 3–4 days. The spectrum ranges from occult bacteremia to fulminant sepsis.

5.1. Meningococcemia (Septicemia)

This is the most severe form, characterized by rapid progression.

• Early Symptoms: Fever, irritability, "flu-like" symptoms (myalgia, leg pain), chills, and sore throat. Leg pain, refusal to walk, and cold hands/feet are important early red flags.
• Cutaneous Signs:
  • Rash: Present in >80% of cases. Initially, it may be a blanching maculopapular rash (often mistaken for a viral exanthem) but rapidly evolves into petechiae and purpura (non-blanching).
  • Purpura Fulminans: Extensive ecchymoses and gangrene of extremities due to DIC and thrombosis. Associated with high mortality.
• Shock: Signs include tachycardia, poor perfusion, hypotension (late sign), and multi-organ failure (adrenal hemorrhage/Waterhouse-Friderichsen syndrome, renal failure, myocardial depression).

5.2. Meningitis

Meningitis occurs in 30–50% of invasive cases, often overlapping with septicemia.

• Presentation: Fever, headache, photophobia, vomiting, and nuchal rigidity.
• Infants: Signs may be subtle, including bulging fontanelle, lethargy, irritability, high-pitched cry, and poor feeding. Kernig’s and Brudzinski’s signs are often absent in young infants.
• Neurologic Signs: Altered mental status, obtundation, and coma. Seizures occur but are less common than in H. influenzae or Pneumococcal meningitis.

5.3. Chronic Meningococcemia

A rare form characterized by intermittent fever, rash, and arthralgia lasting weeks to months. It may spontaneously resolve or progress to acute disease.

5.4. Other Focal Infections

• Pneumonia: Can be primary (airborne transmission) or secondary. More common with serogroup Y.
• Arthritis: Can be septic (early onset) or immune-complex mediated (late onset, sterile effusion).
• Pericarditis: Primary or purulent pericarditis.

6. Diagnosis

Early recognition is critical; treatment should never be delayed for diagnostic testing in suspected cases.

6.1. Laboratory Findings

• Blood Counts: Leukocytosis or leukopenia (poor prognosis), thrombocytopenia (DIC).
• Coagulation: Prolonged PT/PTT, decreased fibrinogen, elevated D-dimer in severe sepsis.
• Biochemistry: Metabolic acidosis, elevated lactate, hypoglycemia, electrolyte disturbances.

6.2. Microbiological Confirmation

1. Blood Culture: Positive in ~50–70% of untreated cases. Yield drops to <5% after antibiotic administration.
2. Cerebrospinal Fluid (CSF):
   • Analysis: Typical bacterial profile—polymorphonuclear pleocytosis, elevated protein (>100 mg/dL), low glucose (<40 mg/dL).
   • Gram Stain: Gram-negative diplococci (intracellular or extracellular). Positive in 75–90% of untreated meningitis.
   • Culture: Gold standard for meningitis diagnosis.
   • Contraindications to LP: Hemodynamic instability (shock), significant coagulopathy, respiratory compromise, or signs of raised intracranial pressure (impending herniation).
3. Skin Lesion Aspirate: Gram stain and culture of petechiae/purpura can be diagnostic even after antibiotic initiation.
4. Polymerase Chain Reaction (PCR): Highly sensitive and specific for detecting meningococcal DNA (e.g., ctrA gene) in blood or CSF. Remains positive for days after antibiotic treatment, significantly increasing confirmation rates.
5. Latex Agglutination: Can detect antigens in CSF but has poor sensitivity compared to PCR and is largely replaced by molecular methods.

7. Treatment

Medical Emergency: If meningococcal disease is suspected in a primary care setting, parenteral antibiotics (e.g., Ceftriaxone or Penicillin G) should be administered immediately before transfer to the hospital, provided venous access is available.

7.1. Antimicrobial Therapy

• Empiric Therapy: Third-generation cephalosporin (Ceftriaxone or Cefotaxime) + Vancomycin (if pneumococcal resistance is suspected) is the standard empiric regimen for bacterial meningitis in children.
• Specific Therapy (once N. meningitidis is confirmed):
  • Drug of Choice: Ceftriaxone (100 mg/kg/day IV once daily or divided q12h; max 4g) or Cefotaxime (200–300 mg/kg/day div q6h). Ceftriaxone is preferred as it eradicates nasopharyngeal carriage.
  • Penicillin G: (300,000–400,000 U/kg/day div q4h). Can be used if the isolate is penicillin-susceptible. However, penicillin does not eradicate carriage; rifampin prophylaxis is required before discharge.
  • Duration: Typically 5–7 days is sufficient for uncomplicated cases.
  • Allergy: Chloramphenicol or Meropenem are alternatives for severe beta-lactam allergy.

7.2. Supportive Care (Critical for Survival)

1. Airway & Breathing: Early intubation for airway protection (coma) or respiratory failure (pulmonary edema, ARDS).
2. Circulation (Shock Management):
   • Aggressive fluid resuscitation (isotonic crystalloids) to treat hypovolemia from capillary leak.
   • Inotropes/Vasopressors: Inotrope support (epinephrine/dopamine) is often required for myocardial depression and vasodilation.
3. Management of Raised ICP: Head elevation, hyperosmolar therapy (mannitol/hypertonic saline), and maintenance of cerebral perfusion pressure.
4. Correction of Coagulopathy: Platelet or FFP transfusion for active bleeding; heparin/Protein C concentrates are generally not recommended due to lack of definitive evidence.

7.3. Adjunctive Therapies

• Steroids: Dexamethasone (0.15 mg/kg q6h) is recommended for pneumococcal and Hib meningitis. Its role in meningococcal meningitis is less clear but generally recommended if given before or with the first dose of antibiotics to reduce neurologic sequelae (hearing loss).

8. Prevention

Prevention relies on chemoprophylaxis of contacts and vaccination.

8.1. Chemoprophylaxis

• Indication: Close contacts of the index case (household members, daycare contacts, direct exposure to secretions via kissing/intubation) within the 7 days preceding illness.
• Timing: Administer as soon as possible (ideally <24 hours).
• Regimens:
  1. Rifampin: Drug of choice for children.
     • <1 month: 5 mg/kg PO q12h x 2 days.
     • $\ge$ 1 month: 10 mg/kg (max 600mg) PO q12h x 2 days.
  2. Ceftriaxone: Single IM dose (125 mg for <15 yrs; 250 mg for >15 yrs). Drug of choice for pregnant women.
  3. Ciprofloxacin: Single oral dose (500 mg) for adults (and children if no resistance reported).

8.2. Immunoprophylaxis (Vaccines)

Vaccination is the most effective control measure.

A. Vaccine Types

1. Polysaccharide Vaccines (MPSV4): (Menomune) Effective against A, C, Y, W. Poorly immunogenic in children <2 years; induces no memory; hyporesponsiveness with repeated doses. Largely replaced by conjugates.
2. Conjugate Vaccines (MenACWY): Polysaccharides conjugated to proteins (Diphtheria toxoid, CRM197, or Tetanus toxoid). Induce T-cell dependent immunity, immune memory, and herd immunity by reducing carriage.
   • MenACWY-D (Menactra) & MenACWY-CRM (Menveo).
   • Schedule: Routine vaccination at 11–12 years with a booster at 16 years. High-risk infants/children (asplenia, complement deficiency) require earlier and multiple doses.
3. Serogroup B Vaccines (MenB): (Bexsero, Trumenba) Recombinant protein vaccines (polysaccharide is non-immunogenic). Recommended for high-risk groups >10 years and during outbreaks.

B. Indications

• Routine: Adolescents (11–12 yrs, booster at 16).
• High Risk: Complement deficiency, asplenia, HIV, microbiologists.
• Travel: Travelers to the "meningitis belt" (sub-Saharan Africa) or Hajj pilgrims (Saudi Arabia requires quadrivalent vaccination).
• Outbreak Control: Vaccination of the at-risk population is crucial during epidemics.

9. Prognosis

• Mortality: 5–10% even with treatment. Higher in adolescents and those with shock.
• Sequelae: Occur in 11–19% of survivors. Includes sensorineural hearing loss (most common), amputations (due to purpura fulminans), skin scarring, and neurologic deficits.
• Poor Prognostic Factors: Shock, purpura fulminans, coma, low WBC (<5000/$m{m}^3$), low platelets (<100,000/$m{m}^3$), young age, and absence of meningitis (pure septicemia).

Summary Table: Treatment of Meningococcal Disease