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Meningococcemia

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Last Update: January 9, 2019.

Introduction

One of the most serious and life-threatening infectious diseases during childhood is bacteremia; a consequence of which is septic shock where inadequate perfusion of tissues occur due to endotoxemia. Neisseria meningitidis (Meningococcus) is an important bacterial infection manifesting as meningitis or septicemia, or more often a combination of both. Asymptomatic pharyngeal colonization is the initial step of infection with humans being the natural reservoirs. From the nasopharynx, the coccus reaches the meninges translocating across the nasopharyngeal mucosa and along the perineural sheath of the olfactory nerve, through the cribriform plate of the ethmoid. Bloodstream spread to the meninges will cause meningitis. In some children, the predominant feature is cardiovascular collapse leading to septic shock.

Transmission occurs by respiratory droplets and requires close direct contact. Children younger than 5 years do not have adequate immunity against the polysaccharide antigens of N. meningitidis. The risk factors for infectious disease in child care facilities include immunologic susceptibility, lack of awareness and practice of good hygiene, a natural tendency to intimacy, frequent oral contact with objects in the environment.

The invasive meningococcal disease is seen in 2 age groups: infants who are vulnerable due to disappearance in the early life of the maternal antibodies and adolescents with a high rate of colonization of the nasopharynx.[1][2]

Etiology

N. meningitidis is a gram-negative coccus, in pairs with adjacent sides flattened. It is non-motile, aerobic, and facultative anaerobic. It produces catalase and is oxidase positive. It produces acid from glucose and maltose. Fresh isolates require enriched media like blood or chocolate agar. Incubation in a humidified 10% carbon dioxide (CO2) environment enhances growth.

Virulence factors include the polysaccharide capsule which enhances invasiveness by inhibiting phagocytosis and enhancing organism survival during bloodstream and central nervous system (CNS) invasion. Pili mediate attachment, colonization, and invasion of the organisms to the mucosal cells of the nasopharynx. Antigenic variation of pili by a cassette mechanism allows the bacterium to escape the host's immune system.

Outer Membrane Proteins

Porin proteins can insert themselves into membranes of target cells, and phagolysosomes can induce apoptosis. OPC protein functions in mucosal adherence and invasion of endothelial cells. IgA1 protease hydrolyzes IgA1 molecules at the hinge regions. The enzyme inactivates IgA1 at mucosal surfaces, enabling initial attachment and subsequent invasion. Pathogenic Neisseria survives and multiplies by their ability to extract iron from high-affinity iron-binding proteins. N. meningitidis can acquire penicillin resistance from commensal Neisseria species in the nasopharynx through DNA fragments by transformation. Meningococcus also exhibit a phase variation of surface antigens, thus evading the host immune response. 

The capsular polysaccharides are antigenic and form the basis of serogroups. Twelve serogroups are A, B, C, H, I, K, L, X, Y, Z, W-135, and 29F. Serogroups A, B, C, W-135, X, and Y are the most common causes of invasive disease worldwide.

Epidemiology

United States

Invasive infections caused by N. meningitidis are reported through the National Notifiable surveillance system in the United States. The number of cases reported to the Centers for Disease Control and Prevention (CDC) in 2013 and 2014 was 556 and 564, respectively. These are the lowest numbers reported in the United States.

In 2014, the overall incidence of invasive meningococcal disease for the United States was 0.14/100,000 population. Of the cases reported, 25% of cases were bacteremia with a fatality of 20%. The serogroup distribution was 26% serogroup B, 36% serogroup C, 9% serogroup Y, and 28% other serogroups. In the United States, serogroup B is responsible for 65% of infant disease, and serogroups C and Y are responsible for adolescent disease. Among the unvaccinated, outbreaks are due to serogroup C.

Meningococcal disease in the United States peaks during the months of November through March. A progressive increase in the protective antibodies against meningococci is seen between 2 and 12 years. Passive in utero IgG antibodies transfer occurs in neonates if the mother has the anti-meningococcal antibody.

International

In developing countries, the incidence rate of invasive meningococcal disease is 10 to 25 per 100,000 inhabitants per year. The highest rate of 10 to 1000 per 100,000 per year is seen in a belt across sub-Saharan Africa, termed the meningitis belt, with recurrent epidemics of group A. Death occurs in 6% to 10% of cases and complications in 4.3 to 11.2% of cases.[3] Group A was predominant during 2007 through 2009, while serogroup W135 predominated in 2010 through 2011.[4] In 2013 and 2014, 2 outbreaks of meningococcal serogroup C, a strain relatively rare in Africa, occurred in Nigeria and Kebbi.[5]

International outbreaks of N. meningitidis infections occurred in 1987 and 2000 associated with the Hajj pilgrimage to Mecca. 1987 outbreak was due to serogroup A and 2000 outbreak due to serogroup W-135. Serogroup W has emerged in other regions, including South America and England. In European countries, invasive serogroup C disease has declined and serogroup B is causing 60% to 72% of cases of invasive disease. In Asia, large epidemics caused by serogroup A occurred historically in China, India, Nepal and Russia, more recently serogroup B and C emerged as the cause in this area.[6]

An increase in the serogroup Y has been reported in the Nordic European countries.[7]

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. Overproduction of nitric oxide lowers arterial pressure due to vasodilation. It also impairs cardiac contractility.

Endothelial cell retraction on interaction with bacterial endothelial cells leads to a loss of integrity causing capillary hemorrhages and formation of thrombi in purpuric lesions. When a large number of bacteria colonize the blood vessels and leads to the corresponding signaling, this is responsible for the extensive purpuric lesions and severity of shock in Purpura fulminans.[8]

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

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 pictures present in some cases.[9][10][11]

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. Twenty percent to 30% of children may not have a rash on presentation.

Chronic meningococcemia is defined as meningococcal septicemia with fever for at least a week before antibiotic therapy and with 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.

Evaluation

Diagnosis should be clinically made, and broad-spectrum antibiotic therapy started with pending organism identification.

Microbiological Diagnosis

  • Public health control
  • Antibiotic sensitivity
  • To exclude other organisms

Gram Stain

Cerebrospinal fluid (CSF) in meningitis shows gram-negative intracellular and extracellular diplococci. 

  • 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
  • Blood culture: 40% to 75% positive before starting treatment. CSF cultures are positive in 90% of untreated patients with meningitis
  • Combining the results of blood and CSF cultures with CSF Gram stain identifies 94% of meningitis antigen

Antigen Detection

  • Meningococcal antigen in CSF (serum and urine have cross-reactions): Latex agglutination; Poor sensitivity and specificity for capsular B type
  • PCR assays can detect meningococcal DNA in CSF, plasma, and serum. Sensitivity and specificity are above 90%. It is more sensitive than blood culture. Diagnosis can be made in 4 to 8 hours. PCR assays are less affected by previous antibiotic therapy.

Imaging

  • If the patient is in a coma, computed tomography (CT) brain imaging is helpful to exclude intracranial hemorrhage.

Hematologic and Metabolic Abnormalities

In meningococcal meningitis, CSF, WBC count, peripheral blood leucocyte count and C-reactive protein, procalcitonin, and ESR are elevated. CSF has raised 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.

Treatment / Management

Antimicrobial Agents

Third-generation cephalosporin-ceftriaxone or cefotaxime are used for initial therapy.

Continued disease:

  • Ceftriaxone (80 mg/kg per day in 1 to 2 divided doses intravenously [IV])
  • Cefotaxime (200 mg/kg per day in 3 to4 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

Recommended duration of therapy is 7 days for both meningitis and meningococcemia.

Adjunctive and Experimental Therapies

Corticosteroid therapy: Replacement doses (25 mg/m3 hydrocortisone 4 times) daily is useful 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 amputation and blood product transfusions and improved functional outcomes.
  • Of other adjunctive therapies in the management of septicemia are plasmapheresis, extracorporeal membrane oxygenation (ECMO), fibrinolysis and anti-mediator therapy.

Emergency Management

  • 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 is monitored and corrected.
  • In cases of raised intracranial pressure, adequate cerebral perfusion should be ensured by correcting shock and providing neurointensive care.

Differential Diagnosis

Infectious

  1. Rocky Mountain spotted fever
  2. Ehrlichiosis
  3. Streptococcal pneumoniae
  4. Hemophilus influenza type B
  5. Group A streptococcus
  6. Staphylococcus aureus
  7. Gram-negative bacterial sepsis with DIC
  8. Infective endocarditis
  9. Gonococcemia
  10. Rat bite fever
  11. Typhus
  12. Secondary syphilis 

Non-Infectious

  1. Henoch-Schonlein purpura
  2. Acute hemorrhagic edema of infancy
  3. Platelet disorders (Idiopathic thrombocytopenic purpura)
  4. Collagen vascular disease
  5. 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 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, 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%.

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 deposition of immune complexes with polysaccharide antigen, IgG, and C3 resulting in acute inflammation.

Pearls and Other Issues

Prophylaxis/Prevention

Vaccine Prevention

Monovalent capsular group C meningococcal conjugate vaccines (MenC) are used in Europe, Australia, and Canada for routine immunization of infants and toddlers. They are highly effective; although a booster at adolescence is advocated.

Quadrivalent meningococcal A, C, Y, W conjugate vaccines (Men ACYW) are used for adolescent immunization in North America. It is being used as a vaccine for high-risk groups and travelers in many countries. It is also replacing Men C as an adolescent booster outside the United States.

Booster doses of Men ACYW are advocated in the United States for high-risk children and person immunized at younger than 15 years of age. Capsular group B outer membrane vesicle (OMV) vaccines are used for outbreaks involving single clones.

Two capsular group B vaccines (Men B-4C, 2 doses, and Men B-FHbp, 3 doses) are licensed for people older than 10 years of age. In the United States, it is recommended for at-risk patients and outbreaks and can be given at 16 to 23 years of age at clinical discretion.

Chemoprophylaxis for Contacts of Patients of Meningococcal Disease

Antibiotic Dose 

Rifampin: 10 mg/kg per dose; Orally every 12 hours for 4 doses (for infants younger than 1 month of age, 5 mg/kg per dose)

Ceftriaxone: Single injection of 125 mg for less than 15 years and 250 mg for older than 15 years*

Ciprofloxacin: 20 mg/kg (max 500 mg) older than 1 month of age*

* From American Academy of Pediatrics Committee on Infectious Disease. Red book 2015 Report of the Committee on Infectious Diseases, 30th edition. Elk Grove, IL, American Academy of Pediatrics 2015.

Questions

To access free multiple choice questions on this topic, click here.

References

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Coureuil M, Join-Lambert O, Lécuyer H, Bourdoulous S, Marullo S, Nassif X. Pathogenesis of meningococcemia. Cold Spring Harb Perspect Med. 2013 Jun 01;3(6) [PMC free article: PMC3662350] [PubMed: 23732856]
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Bosis S, Mayer A, Esposito S. Meningococcal disease in childhood: epidemiology, clinical features and prevention. J Prev Med Hyg. 2015 Aug 31;56(3):E121-4. [PMC free article: PMC4755120] [PubMed: 26788732]
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Harrison LH. Epidemiological profile of meningococcal disease in the United States. Clin. Infect. Dis. 2010 Mar 01;50 Suppl 2:S37-44. [PMC free article: PMC2820831] [PubMed: 20144015]
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Funk A, Uadiale K, Kamau C, Caugant DA, Ango U, Greig J. Sequential outbreaks due to a new strain of Neisseria meningitidis serogroup C in northern Nigeria, 2013-14. PLoS Curr. 2014 Dec 29;6 [PMC free article: PMC4322033] [PubMed: 25685621]
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Törös B, Thulin Hedberg S, Jacobsson S, Fredlund H, Olcén P, Mölling P. Surveillance of invasive Neisseria meningitidis with a serogroup Y update, Sweden 2010 to 2012. Euro Surveill. 2014 Oct 23;19(42) [PubMed: 25358044]
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Branco RG, Tasker RC. Meningococcal meningitis. Curr Treat Options Neurol. 2010 Sep;12(5):464-74. [PubMed: 20842601]
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Dass Hazarika R, Deka NM, Khyriem AB, Lyngdoh WV, Barman H, Duwarah SG, Jain P, Borthakur D. Invasive meningococcal infection: analysis of 110 cases from a tertiary care centre in North East India. Indian J Pediatr. 2013 May;80(5):359-64. [PubMed: 22821284]
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