Meningococcal Disease (Neisseria meningitidis Infection)

Etiology

N meningitidis is an aerobic or facultative anaerobic, gram-negative diplococcus that exclusively infects humans (see Image. Diplococci).[5] There are at least 12 serotypes based on unique capsular polysaccharides of N meningitidis, with serotypes A, B, C, W, X, and Y responsible for the majority of meningococcal infections. Serotypes A and C are the main serotypes responsible for meningococcal disease in Africa. Serotypes B, C, and Y are the main serotypes causing disease in Europe, the United States, and Canada.[6] Serotype W is responsible for epidemic outbreaks worldwide and is associated with the Hajj pilgrimages to Saudi Arabia.[7]

N meningitidis is a common and significant cause of community-acquired bacterial meningitis in the United States, affecting children and adults. This infection can be devastating, with a high mortality rate, and is the second most common cause of community-acquired bacterial meningitis in adults, following Streptococcus pneumoniae.[8] Other infections that N meningitidis can cause include meningococcemia (a bloodstream infection caused by the bacterium), pneumonia, septic arthritis, pericarditis, and urethritis. In addition, N meningitidis can also cause endemic and epidemic infections, affecting young, healthy adults.[6] 

Epidemiology

In the United States, meningococcal disease incidence peaks between November and March.[9] The incidence of meningococcal disease has decreased with the routine administration of meningococcal vaccination. The incidence of meningococcal disease decreased from 1.2 cases per 100,000 individuals in 1996 to 0.1 cases per 100,000 individuals in 2018.[6] However, the United States Centers for Disease Control and Prevention reported an increase in meningococcal disease in 2022 among individuals living with HIV, a group that has historically had low meningococcal vaccine coverage rates.[10]

The highest incidence of meningococcal disease appears in infants younger than 1 (2.45 cases per 100,000 individuals).[11] N meningitidis can cause endemic and epidemic outbreaks and is a significant cause of bacterial meningitis in sub-Saharan Africa, a region often referred to as the meningitis belt.[6] The mortality rate varies from approximately 10% to 14% among patients who receive treatment and can reach up to 50% among patients who do not receive treatment.[12]

Pathophysiology

Humans are the exclusive hosts of N meningitidis, carrying the pathogen in their nasopharynx before the onset of systemic infection. Colonized humans may be asymptomatic carriers.[2] Nasopharyngeal colonization increases the risk of transmission to individuals in close contact with infected patients, such as family members, college roommates, and military recruits, placing them at higher risk of acquiring N meningitidis infection. Individuals involved in laboratory or clinical care are also at heightened risk, particularly when exposed to aerosolized particles during procedures like intubation without appropriate protective equipment, such as masks or face shields. The incubation period varies and ranges from 1 to 14 days.[13]

Following colonization, several virulence factors help the bacterium invade human cells and the immune system. The polysaccharide capsule enhances invasiveness by inhibiting phagocytosis and enhancing the organism's survival during the invasion of the bloodstream and central nervous system. Pili mediate attachment, colonization, and invasion of the organisms to the mucosal cells of the nasopharynx. The antigenic variation of pili by a cassette mechanism allows the bacterium to escape the host's immune system.[14] Lipooligosaccharide acts as an endotoxin and activates the proinflammatory cytokine pathway of the host to cause meningococcal sepsis.[15] Lipooligosaccharide interacts with host immune cells to initiate the release of inflammatory mediators such as tumor necrosis factor-alpha, interleukin-1 (IL-1), IL-6, and interferon-gamma to cause shock.[16] Once in the bloodstream, N meningitidis induces a robust immune response, leading to endothelial damage, capillary leakage, tissue necrosis, organ failure, and ultimately meningococcal sepsis. Bloodstream invasion is considered to be the primary route to the brain, but N meningitidis can also cross the cribriform plate of the ethmoid bone.[17]

Similar to many other diseases, the immune system is essential in protecting the host against meningococcal infection. Certain health conditions that compromise the human immune system elevate the risk of contracting meningococcal diseases, such as meningococcemia and meningitis. These conditions include HIV infection, AIDS, asplenia, and complement deficiencies.[5]

History and Physical

The clinical presentation of N meningitidis can vary widely and may initially appear benign, making it difficult to diagnose, especially in areas with no reported epidemics. Typically, the initial presentation of meningococcal meningitis can include the sudden onset of fever, headache, nausea, vomiting, severe myalgias, nonspecific rash, sore throat, and other upper respiratory symptoms. These symptoms may be confused with a variety of other illnesses. The potential for rapid disease progression, especially given the possibility of death within hours of symptom onset, makes early identification of meningococcal disease challenging due to its low incidence and nonspecific early symptoms. As the disease progresses, more specific signs may develop, including neck stiffness, photophobia, petechiae or hemorrhagic rash, altered mental status, shock, abnormal skin color, purpura fulminans, or even disseminated intravascular coagulation.[13]

Vital signs may include hypotension and tachycardia, which indicate early signs of sepsis. A comprehensive physical examination should be performed, including a thorough skin inspection for any signs of a rash. The rash, a distinguishing feature, may initially appear as small lesions that may appear urticarial, macular, or papular. The rash can develop into petechiae, purpura, or ecchymosis (see Image. Petechiae). These findings may be early signs of thrombocytopenia, purpura fulminans, and disseminated intravascular coagulation.[13]

Meningeal irritability can be confirmed by provocative tests such as the Kernig and Brudzinski signs. The Kernig sign is positive if the patient has muscular resistance or pain when the knee is extended beyond 135° while in the supine position with the hip flexed.[18] Similarly, the Brudzinski sign is positive when the supine patient shows reflex flexion of the hips and knees after passive neck flexion.[18] Although these signs are classic signs of meningitis, their respective sensitivities of 55.5% and 53.3% make them unreliable in excluding meningitis.[19] A thorough neurologic examination should be performed, focusing on alterations in mental status and focal deficits. 

When considering signs and symptoms of the disease, it is essential to note that the classic triad of fever, altered mental status, and nuchal rigidity is rare, occurring in only about 44% of cases. However, when 2 of the 4 symptoms, including headache, altered mental status, neck stiffness, and fever, were present, 95% of patients ultimately diagnosed with meningitis were identified.[20] Clinicians should consider N meningitidis infection in patients with a sudden onset of fever who display early signs of sepsis, rapidly progressing disease, and rash.

Purpura fulminans, a complication of meningococcal disease resulting from vascular collapse, is characterized by cutaneous hemorrhage and skin necrosis due to vascular thrombosis and disseminated intravascular coagulation. Typically, petechiae and erythema are observed on the skin but can progress to ecchymosis and eventually painful areas of necrosis, with the development of bullae and vesicles. Gangrenous necrosis can occur and be severe, often requiring limb amputation. Atypical skin color, cold hands and feet, and painful legs may be the signs of vascular compromise.[13]

Meningococcal pneumonia occurs in 5% to 15% of individuals with meningococcal disease and typically presents with symptoms similar to community-acquired pneumonia, such as fever, chills, and pleuritic chest pain. Less than 1 in 3 patients with meningococcal pneumonia present with a productive cough, and less than 1 in 4 will report shortness of breath. Although a rash may be observed in some patients, meningococcal pneumonia rarely coexists with meningococcemia.[21]

Since the mid-2010s, an increase in cases of meningococcal urethritis has been reported, predominantly in young heterosexual men with purulent urethral discharge and dysuria.[22][23][24] A sentinel surveillance site for gonococcal disease surveillance reported that 20% of men with urethritis and gram-negative intracellular diplococci were ultimately diagnosed with meningococcal urethritis.[24] Therefore, meningococcal urethritis should be considered in the differential diagnosis of urethritis.

Meningococcal arthritis may occur either as septic arthritis caused by N meningitidis infection of the joint fluid or as secondary reactive arthritis related to joint immune complexes.[25] The prevalence of arthritis among persons with meningococcal disease is not yet well understood but has been reported to range from 2% to 12.5%.[25] Meningococcal arthritis may occur with or without meningitis.[26] Joint symptoms include pain, redness, swelling, and warmth.[25] The knee is the most commonly affected joint, followed by the wrist and ankle.[27]

Meningococcal pericarditis is a rare condition that may present either as primary pericarditis with meningococcal infection limited to the pericardium, as disseminated meningococcal disease affecting multiple infection sites including the pericardium, or late-stage reactive pericarditis resembling post-viral pericarditis. Accurate identification of meningococcal pericarditis is critical, as treatment and prognosis vary depending on the cause.[28]

Evaluation

A lumbar puncture is the preferred diagnostic method for identifying meningitis and should be prioritized to facilitate prompt evaluation and diagnosis. Evidence of elevated intracranial pressure, such as altered mental status, new-onset seizure within 1 week of symptoms, papilledema, an immunocompromised state, or focal neurologic deficit; coagulopathy; and cardiorespiratory insufficiency are contraindications to performing a lumbar puncture. Antibiotic therapy should be initiated promptly, even before lumbar puncture completion, for patients where meningitis is highly suspected.[12] Although parenteral antibiotic therapy can eliminate meningococci from CSF in less than 6 hours, blood cultures and CSF studies can still be useful even after antibiotic initiation.[29] CSF analysis should include Gram staining, culture, glucose level, cell count, and protein concentration. CSF findings that suggest bacterial meningitis include high opening pressure, decreased glucose levels (less than 45 mg/dL or less than 2.5 mmol/L), polymorphonuclear pleocytosis (white blood count more than 1000/µL), increased protein levels (more than 500 mg/dL), and a CSF-to-serum glucose ratio of less than 0.4 (see Table. Expected CSF Findings in Bacterial versus Viral versus Fungal Meningitis).[13] 

Table 1. Expected CSF Findings in Bacterial, Viral, and Fungal Meningitis

Abbreviation: WBC, white blood count.

CSF Gram staining, polymerase chain reaction (PCR), and latex agglutination may aid in confirmation, particularly in patients with negative CSF cultures after antibiotic pretreatment. Gram staining is diagnostic in 85% of patients with meningococcal meningitis. PCR detects strands of bacterial DNA, not requiring an intact bacterium for detection, whereas latex agglutination detects capsular antigens.[30] CSF culture is the gold standard for the diagnosis of bacterial meningitis.[30]

Computed tomography imaging may assist in the diagnosis of patients with altered mental status, mainly to rule out other diagnoses under consideration.[12] If imaging is necessary, it is crucial to coordinate with the nursing team and imaging suite to avoid delaying antibiotic administration.

Treatment / Management

Early recognition and treatment of meningococcal infections are critical for improving outcomes. The primary focus in treating meningococcal infection includes administering antibiotics, implementing isolation and droplet precautions, consulting with infectious disease specialists, management in the intensive care unit (ICU), management of coagulopathies, and identifying individuals at risk who may have been exposed to N meningitidis.[12]

Because meningococcal meningitis can present similarly to other bacterial meningitides, empiric treatment should be initiated while awaiting culture results. This preemptive approach includes a third-generation cephalosporin such as ceftriaxone or cefotaxime and broad-spectrum antibiotics such as vancomycin pending bacterial identification. If the culture identifies the organism as penicillin-susceptible, treatment can be switched to penicillin G. However, continuing third-generation cephalosporin treatment is also an option. For patients who have significant allergies to penicillin and other beta-lactams, chloramphenicol may be used as an alternative. The duration of antibiotic therapy is typically 5 to 6 days.[12][31][32] Droplet precautions should be maintained for at least 24 hours after initiating effective antibiotic therapy.(A1)

Dosages

• Ceftriaxone dosing is 2 g for adults and 50 mg/kg for pediatric patients older than 1 month, administered intravenously (IV) every 12 hours. In contrast, cefotaxime dosing is 2 g every 4 to 6 hours for adults and 50 mg/kg for pediatric patients older than 1 month, given every 6 hours.[12]
  • Third-generation cephalosporins are generally preferable due to their high efficacy and simpler dosing regimens.

• Penicillin G dosing is 4 million units every 4 hours IV for adults and pediatric patients older than 1 month.[12]

• Chloramphenicol dosing is 50 mg/kg IV 4 times daily.[12]
  • Serum concentrations require monitoring because of the risk of chloramphenicol toxicity.[33]
  • Persistently elevated serum concentrations of chloramphenicol above 50 mg/L have been associated with gray-baby syndrome, consisting of ashen-gray skin discoloration, abdominal distention, respiratory distress, and hemodynamic collapse. Although neonates are at the highest risk, gray syndrome can occur in any age group if hepatic or renal function is impaired or excessive doses are administered.[34]
  • In the United States, chloramphenicol is classed as pregnancy category C, and its use should be avoided during breastfeeding.[35]
(B3)

• High-dose dexamethasone should be administered at the initial suspicion of bacterial meningitis due to its protective benefits in pneumococcal meningitis.[12][36] Dexamethasone should be administered IV within 4 hours before but no more than 12 hours after the first dose of IV antibiotics. The dosage should be 0.15 mg/kg every 6 hours up to a maximum dosage of 10 mg every 6 hours.[12][31] However, dexamethasone has no therapeutic benefit in meningococcal meningitis and should be discontinued once this diagnosis is established.[36][31]

Patients with meningococcal infection require prompt and aggressive supportive care, particularly in cases of sepsis or septic shock. Management may include intravenous fluid resuscitation and the use of vasopressors such as norepinephrine.[31] Early intubation should be considered in patients with evidence of airway compromise, ongoing shock, intractable seizures, or elevated intracranial pressure.[37] Patients showing signs of disseminated intravascular coagulation may require aggressive hydration, blood transfusions, platelet replacement, and possibly coagulation factor replacement. Although researchers have proposed protein C as an adjuvant treatment, its use remains controversial and is not widely practiced.[12]

Differential Diagnosis

S pneumoniae is the most common cause of bacterial meningitis in the United States and should be included in the differential diagnosis for patients suspected of having meningococcal meningitis. Less common causes of bacterial meningitis include Haemophilus influenzae, group B Streptococcus, and Listeria monocytogenes.[30] Other potential causes of meningitis include viral, tuberculous, eosinophilic, and fungal meningitis, as well as noninfectious causes such as malignancy.[38]

Clinicians examining adults with a maculopapular rash and fever should consider alternate etiologies, including infectious mononucleosis, West Nile virus, Zika virus, HIV, Ebola virus, Rocky Mountain spotted fever, ehrlichiosis, and hypersensitivity drug reactions.[39] In addition, children with a maculopapular rash and fever should be considered for a differential diagnosis that includes Kawasaki disease, measles, scarlet fever, rubella, parvovirus B19, roseola, Epstein-Barr virus, and hand, foot, and mouth disease.[40]

Prognosis

Although the mortality rate of meningococcal infection can be as high as 50% in untreated patients, early and aggressive treatment can reduce the mortality rate to approximately 10% to 14%. Early administration of antibiotics is crucial in determining a good outcome of meningococcal infection. Even with treatment, long-term complications can still occur in 11% to 19% of survivors.[12] Poor prognostic factors in patients with meningococcal meningitis include Shock, presence of focal deficits, mental obtundation or coma, purpuric or ecchymotic rash, absence of meningeal signs, low or normal blood leukocyte count, age older than 60 years, presence of anemia, thrombocytopenia, low erythrocyte sedimentation rate (or C-reactive protein level), low blood concentrations of antithrombin or proteins S and C, high blood levels of plasminogen activator inhibitor 1, malignancy, intracranial bleed, and cerebrovascular accident.[20]

Complications

Common complications of meningococcal disease include chronic pain, skin scarring, limb amputation, and neurological impairments, ranging from hearing and visual impairments to motor function impairments. Urgent complications of meningococcal disease include septic shock, purpura fulminans, seizures, hydrocephalus, cerebral venous sinus thrombosis, acute adrenal crisis due to adrenal hemorrhage (Waterhouse-Friderichsen syndrome), and subdural empyema.[31] Hearing impairment and amputations occur in approximately 3% of cases, arthritis in 10% of cases, and post-infection inflammatory syndrome in 6% to 15% of cases.[12] Up to one-third of survivors of meningococcal disease experience psychological disorders, such as posttraumatic stress disorder, anxiety, and depression, requiring follow-up care with psychologists and psychiatrists.[12]

As with any critical illness, other complications may include prolonged ventilator weaning, tracheostomy care, feeding tube care, prolonged physical and occupational rehabilitation, critical illness polyneuropathy and myopathy, and secondary infections and wounds.