Meningococcemia

Etiology

N. meningitidis is a gram-negative coccus in pairs with adjacent sides flattened. This nonmotile, aerobic, facultatively anaerobic pathogen is classified into 12 serogroups based on its capsular polysaccharide. Serogroups A, B, C, W-135, X, and Y are the most common causes of invasive disease worldwide.[5] Please see StatPearls' companion resource, "Meningococcal Disease (Neisseria Meningitidis Infection)", for further information on the microbiology and etiology of meningococcal disease.

Epidemiology

In the United States, invasive N. meningitidis infections are reported through the National Notifiable Diseases Surveillance System. The incidence of meningococcal disease has steadily declined in the United States since the introduction of routine and booster meningococcal vaccines.[6] 

Internationally, the highest incidence rate of invasive meningococcal disease is seen in a belt across sub-Saharan Africa, termed the meningitis belt, where serogroups A and W-135 predominate.[7] International outbreaks of N. meningitidis infections have occurred in association with the Hajj pilgrimage to Mecca.[8]  Please see StatPearls' companion resource, "Meningococcal Disease (Neisseria Meningitidis Infection)", for further information on the incidence and mortality of meningococcal disease.

Pathophysiology

The primary cause of cardiovascular collapse from sepsis is a peripheral circulatory failure. Cardiac dysfunction due to myocardial failure plays a prominent role in meningococcal disease. Higher endotoxin (LOS) concentrations were associated with shock, renal failure, and respiratory distress. High concentrations of IL-6 and IL-8 are seen in those with meningococcal shock. TNF and IL-1 activate endothelial cells by increasing their permeability and adhesiveness for white cells. The overproduction of nitric oxide lowers arterial pressure due to vasodilation and also impairs cardiac contractility.

Endothelial cell retraction on interaction with bacterial endothelial cells leads to a loss of integrity, causing capillary hemorrhages and the formation of thrombi in purpuric lesions. When a large number of bacteria colonize the blood vessels and lead to the corresponding signaling, this is responsible for the extensive purpuric lesions and severity of shock in Purpura fulminans.[9]

Histopathology

Histology of skin lesions shows endothelial necrosis of capillaries and small veins in the dermis and subcutaneous tissue. Neutrophil infiltration and occlusion of vessels with WBCs, platelets, fibrin thrombi, and hemorrhage are seen. Meningococci are seen within the endothelium and thrombi.

History and Physical

Clinical Features of Meningococcemia

The disease spectrum caused by N. meningitidis ranges from asymptomatic carriage to death due to fulminant meningococcemia. Meningococcal meningitis and septicemia are the common syndromes reported, although both clinical presentations manifest in some cases.[10][11][12]

The signs and symptoms of meningococcemia include an early upper respiratory tract infection with coryza, pharyngitis, tonsillitis, and laryngitis. Patients are febrile with a headache, vomiting, and lethargy. Typically, patients with meningococcemia have a fever and hemorrhagic rash, followed by signs of severe circulatory collapse. Purpura and shock often develop within hours. Diffuse mottling to extensive purpuric lesions are the skin manifestations. Petechiae or purpura are seen in 50% to 60% of patients. Approximately 20% to 30% of children may not have a rash on presentation.[13]

Chronic meningococcemia is defined as meningococcal septicemia with fever for at least a week before antibiotic therapy and no meningeal symptoms. In chronic meningococcemia, bacteria are never found by biopsy or culture of skin lesions. Researchers postulate that the skin changes and arthritis may result from antigen-antibody complexes. The diagnosis is established by identifying the organism in blood cultures. Recovery is prompt following antibiotic therapy.[14]

Several investigators have stressed myocardial manifestations associated with meningococcal meningitis, including heart failure with pulmonary edema and high central venous pressures accompanying signs of poor peripheral perfusion. Treatment of myocardial failure can ameliorate the situation. Increased levels of interleukin 6 may be a mediator of myocardial depression in septic shock due to meningococcal infection.[15]

Evaluation

Diagnosis should be clinically made, and broad-spectrum antibiotic therapy should be started while awaiting organism identification. Additionally, after initial clinical diagnosis, prompt microbiological testing should be conducted for public health control, to assess antibiotic sensitivity, and to exclude other microorganisms.

Laboratory Studies

Gram stain

Cerebrospinal fluid (CSF) in patients with meningitis shows findings of gram-negative intracellular and extracellular diplococci. Other findings can include:

• Skin lesions in meningococcemia: Needle aspiration and scrapings are gram-stained
• Buffy coat of blood gram stain

Culture

CSF is inoculated onto chocolate agar and incubated in 3% to 5% CO₂. Specimens from mucosa are inoculated into selective medium-Thayer-Martin chocolate agar to which vancomycin, colistin, and nystatin are added to inhibit commensals. An estimated 40% to 75% of blood cultures are positive before starting treatment. CSF cultures are positive in 90% of untreated patients with meningitis. Combining the blood and CSF culture results with a CSF gram stain identifies 94% of meningitis antigens.

Antigen detection

Polymerase chain reaction (PCR) assays can detect meningococcal DNA in CSF, plasma, and serum with sensitivity and specificity of >90%. Furthermore, PCR is more sensitive than blood culture. PCR can typically confirm the diagnosis within 4 to 8 hours. Additionally, PCR assays are less affected by previous antibiotic therapy.

However, due to its poor sensitivity and specificity for capsular B type, latex agglutination testing is not recommended for routine use by the Infectious Diseases Society of America (IDSA). However, it may be helpful in some patients with suspected meningococcal infection who have negative CSF gram stains and cultures following antibiotic pretreatment.[16] 

Additional laboratory findings

Hematologic and metabolic laboratory abnormalities are also characteristic of meningococcal meningitis and septicemia. CSF, white blood cell count, peripheral blood leukocyte count, C-reactive protein, procalcitonin, and ESR are elevated in meningococcal meningitis. CSF also demonstrates elevated protein, low glucose, and gram-negative Diplococcus.

In meningococcal septicemia, metabolic derangements like hypoglycemia, hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, and metabolic acidosis are seen in severe cases. Anemia, coagulopathy, decreased protein C, fibrinogen, prothrombin, and coagulation factors (V, VII, and X) are also seen.

Imaging Studies

In comatose patients, computed tomography (CT) brain imaging is helpful to exclude intracranial hemorrhage.

Treatment / Management

Antimicrobial Agents

According to the National Institute for Health and Care Excellence guidelines 2024, third-generation cephalosporin-ceftriaxone is recommended for initial therapy. Chloramphenicol is used for severe antibiotic allergy to beta-lactams.[17] Ceftriaxone should not be used in premature babies or infants with acidosis, jaundice, or hypoalbuminemia, as it may worsen hyperbilirubinemia.[18] According to the European Society of Clinical Microbiology and Infectious Diseases, ceftriaxone/cefotaxime is preferred for penicillin resistance. Meropenem, cefipime, ciprofloxacin, or chloramphenicol can be an alternative.[19] The Infectious Diseases of America 2004 guidelines state that third-generation cephalosporin, such as ceftriaxone/cefotraxime, is preferred.[16] At last, the CDC 2024 states that the empirical therapy for suspected meningococcal disease is an extended-spectrum cephalosporin (ceftriaxone/cefotaxime). Treatment with penicillin/ampicillin requires susceptibility testing. https://www.cdc.gov/meningococcal/hcp/clinical-guidance/index.html#:~:text=Empirical%20therapy%20for%20suspected%20meningococcal,needed%20to%20eradicate%20nasopharyngeal%20carriage.(A1)

• Ceftriaxone 80 mg/kg per day in 1 to 2 divided doses intravenously (IV)
• Cefotaxime 200 mg/kg per day in 3 to 4 divided doses IV
• Penicillin G 50 mg/kg every 4 to 6 hours IV
• Chloramphenicol 100 mg/kg/day in 4 divided doses, orally or IV
• Meropenem for those with severe allergies

The recommended duration of therapy is 7 days for both meningitis and meningococcemia.[19]

Adjunctive and Experimental Therapies

Corticosteroid therapy using replacement doses of hydrocortisone 25 mg/m³ 4 times daily is helpful in children with refractory shock associated with impaired adrenal gland response.

Recombinant bactericidal permeability-increasing protein (rBPI) binds to endotoxin and blocks the inflammatory cascade. Children receiving rBPI had fewer amputations and blood product transfusions and improved functional outcomes. Other adjunctive therapies in the management of septicemia are plasmapheresis, extracorporeal membrane oxygenation (ECMO), fibrinolysis, and antimediator therapy.

Emergency Management

The following supportive measures should be performed for acute management of meningococcal disease:

• After securing the airway, priorities in children with meningococcal disease are:
  • Correction of cardiovascular shock and 
  • Control of raised intracranial pressure
• Aggressive fluid resuscitation with 0.9% NaCl solution in a volume of 20 mL/kg over 5 to 10 minutes is of importance and repeated until shock improves. Inotropic support is needed to maintain tissue perfusion.
• Human albumin solution can be used as an alternative.
• Anemia, coagulopathy are monitored and corrected.
• In cases of raised intracranial pressure, adequate cerebral perfusion should be ensured by correcting shock and providing neurointensive care.

Differential Diagnosis

The following differntial diagnoses should be considered when evaluating patients with suspected meningococcemia:

Infectious

• Rocky Mountain spotted fever
• Ehrlichiosis
• Streptococcal pneumoniae
• Hemophilus influenza type B
• Group A streptococcus
• Staphylococcus aureus
• Gram-negative bacterial sepsis with DIC
• Infective endocarditis
• Gonococcemia
• Rat-bite fever
• Typhus
• Secondary syphilis 

Noninfectious

• Henoch-Schonlein purpura
• Acute hemorrhagic edema of infancy
• Platelet disorders (Idiopathic thrombocytopenic purpura)
• Collagen vascular disease
• Neoplastic processes

Prognosis

Scoring systems are devised to predict prognosis with meningococcal disease. Most prognostic scoring systems agree that purpura fulminans and shock are poor prognostic signs. The Glasgow meningococcal septicemia prognostic score (GMSPS) evaluates the following 7 key items: hypotension, the difference in skin-core temperature, coma, acute deterioration, the absence of meningismus, progressive purpura, and base deficit. At Los Angeles Children's Hospital, the following 5 features were correlated with a poor prognosis: shock or seizures, hypothermia, total WBC count less than 5000/mm, platelet count less than 100,000/mm, and development of Purpura fulminans.

The overall mortality of invasive meningococcal disease in the United States is 7% to 19%. A retrospective population-based analysis of meningococcal disease mortality in the United States from 1990 to 2002 identified 3335 meningococcal deaths.

Complications

Sequelae of meningococcemia are skin necrosis (ischaemic infarction of skin and soft tissues), hearing loss, deafness, seizure, amputation, and skin scarring. Impaired organ perfusion due to hypovolemia, vasoconstriction, and myocardial failure result in prerenal failure manifesting as oliguria or anuria or acute tubular necrosis.

Immunologic or reactive complications like arthritis, cutaneous vasculitis, iritis, and pericarditis are due to the deposition of immune complexes with polysaccharide antigen, IgG, and C3, resulting in acute inflammation.