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Meningococcemia

  • Author: Mahmud H Javid, MBBS; Chief Editor: John L Brusch, MD, FACP  more...
 
Updated: Oct 14, 2015
 

Practice Essentials

Meningococcemia is defined as dissemination of meningococci (Neisseria meningitidis) into the bloodstream (see the image below). Patients with acute meningococcemia may present with (1) meningitis (2) meningitis with meningococcemia, or (3) meningococcemia without clinically apparent meningitis.

A 9-month-old baby in septic shock with purpuric N A 9-month-old baby in septic shock with purpuric Neisseria meningitis skin lesions. Photo by D. Scott Smith, MD, taken at Stanford University Hospital.

See Pediatric Vaccinations: Do You Know the Recommended Schedules?, a Critical Images slideshow, to help stay current with the latest routine and catch-up immunization schedules for 16 vaccine-preventable diseases.

Signs and symptoms

Patients with acute meningococcemia may present with meningitis alone, meningitis and meningococcemia, meningococcemia without clinically apparent meningitis.

The clinical presentation of meningococcemia may include any of the following:

  • A nonspecific prodrome of cough, headache, and sore throat
  • The above followed by a few days of upper respiratory symptoms, increasing temperature, and chills
  • Subsequent malaise, weakness, myalgias, headache, nausea, vomiting, and arthralgias
  • The characteristic petechial skin rash is usually located on the trunk and legs and may rapidly evolve into purpura (see the image below)
  • Scattered petechiae in a patient with acute mening Scattered petechiae in a patient with acute meningococcemia.
  • In fulminant meningococcemia, a hemorrhagic eruption, hypotension, and cardiac depression, as well as rapid enlargement of petechiae and purpuric lesions (see the image below)
  • Child with severe meningococcal disease and purpur Child with severe meningococcal disease and purpura fulminans.

The meningitis of meningococcemia is associated with the following[1] :

  • Headache
  • Fever
  • Vomiting
  • Photophobia
  • Lethargy
  • Neck stiffness
  • Rash (more than 50% of cases)
  • Seizures (20% of patients at presentation and an additional 10% of patients within 72 hours)
  • Early nonspecific symptoms

Meningococcemia is characterized by the following[2] :

  • Fever
  • Initial rash that may be erythematous or maculopapulars, short lived, followed by petechiae and purpura
  • Vomiting
  • Headache
  • Myalgias that may be quite severe
  • Sore throat
  • Abdominal pain
  • Tachycardia/tachypnea
  • Hypotension
  • Cool extremities
  • Initially normal level of consciousness
  • Early symptoms indistinguishable from those associated with viral illness, such as influenza or streptococcal pharyngitis; however, this infection accelerates at a rate matched by few other infections

Physical findings may include the following:

  • Dermatologic manifestations: Petechiae, rash, ecchymoses, purpura
  • Meningococcal meningitis: Pain and resistance to neck flexion, other signs of meningeal irritation, petechiae, fever (of variable intensity)
  • Fulminant meningococcemia: Purpuric eruption, hemorrhages on buccal mucosa and conjunctivae, no signs of meningitis, cyanosis, hypotension, profound shock, high fever, pulmonary insufficiency
  • Meningococcal septicemia: Fever, rash, tachycardia, hypotension, cool extremities, initially normal level of consciousness

See Clinical Presentation for more detail.

Diagnosis

Laboratory findings in the early stages of meningococcal disease are often nonspecific. Definitive diagnosis requires retrieval of meningococci from blood, cerebrospinal fluid, joint fluid, or skin lesions. Studies may include the following:

  • Complete blood count with white blood cell count
  • Blood urea nitrogen and creatinine
  • Fibrinogen and C-reactive protein
  • Coagulation studies
  • Electrolytes
  • Tests for end-organ damage
  • Blood and throat cultures
  • Imaging studies: Chest radiography, echocardiography, magnetic resonance imaging
  • Needle aspiration and skin biopsy
  • Lumbar puncture and CSF analysis
  • Serogrouping/serotyping

See Workup for more detail.

Management

Clinical guideline summaries related to meningococcal disease include the following:

  • American Academy of Pediatrics Committee on Infectious Diseases [3]
  • Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) [4]
  • Scottish Intercollegiate Guidelines Network [5]

Patients with a rash consistent with meningococcemia should be started immediately on parenteral antibiotics, especially in the setting of factors that are associated with poor clinical outcomes, as follows:

  • Shock
  • Absence of meningitis
  • Rapidly extending rash
  • Low WBC count
  • Coagulopathy
  • Deteriorating level of consciousness
  • Increased intracranial pressure (ICP)

Antibiotics recommended for the treatment of meningococcemia include the following:

  • Third-generation cephalosporins such as ceftriaxone (2 g IV q24h) or cefotaxime (2 g IV q4-6h) are the preferred antibiotics
  • Alternative agents include (1) ampicillin 12 g/d either by continuous infusion or by divided dosing q4h or (2) moxifloxacin 6-8 g/d IV
  • The course of therapy is 7-10 days
  • Note: Meningococci are resistant to vancomycin and the aminoglycosides
  • Chloramphenicol may be considered in patients who are allergic to beta-lactam antibiotics. It appears to be most useful when administrated as a single IM injection during epidemics in developed countries.

See Treatment and Medication for more detail.

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Background

N meningitidis is an encapsulated gram-negative diplococcus (seen in the image below). There are at least 13 serogroups of the bacterium, with the most important being serogroups A, B, C, and W-135. (See Pathophysiology, Etiology, and Workup.)

Gram-negative intracellular diplococci. Courtesy P Gram-negative intracellular diplococci. Courtesy Professor Chien Liu.

Patients with acute meningococcemia may present with 1 of 3 syndromes: meningitis, meningitis with meningococcemia, or meningococcemia without obvious meningitis.[6] Of cases of invasive meningococcal disease, 30%-50% present with meningitis alone, 40% have meningitis with bacteremia, and 7%-10% have invasion of the bloodstream alone. (See Presentation and Workup.) N meningitides remains a major infectious cause of childhood death in developed countries. The mortality rate remains around 10%, although, in some specialist centers, it has decreased to less than 5%overall. There has been little improvement in morbidity and mortality since the beginning of the antibiotic era because of the inability of antimicrobials to prevent the cardiovascular collapse brought about by the organism’s endotoxin.[7]

Dorsum of the hand showing petechiae. Courtesy of Dorsum of the hand showing petechiae. Courtesy of Professor Chien Liu.

Carriers

Approximately 2% of children younger than 2 years, 5% of children up to 17 years, and 20-40% of young adults are carriers of N meningitidis. Overcrowded conditions (eg, schools, military camps) can significantly increase the carrier rate. (See Pathophysiology, Etiology, and Epidemiology.)

Screening of military recruits performed during recent epidemics demonstrated that, although as many as 95% of recruits were oropharyngeal carriers, only 1% developed systemic disease. Because very few of those infected had ever been in contact with another patient with a similar history, asymptomatic carriage is thought to be the major source of transmission of pathogenic strains. (See Pathophysiology and Etiology.)

Immunity to N meningitidis appears to be acquired through intermittent nasal carriage of meningococci and by antigenic cross-reaction with enteric flora during the first 2 decades of life.

Chronic meningococcemia

Chronic meningococcemia is a rare (<200 documented cases) clinical presentation of N meningitidis that is most often observed in adults. In this condition, painful skin lesions similar to those seen in in gonococcemia are present on the extremities, with migratory polyarthritis and tenosynovitis. Antibiotic treatment results in a prompt response.

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Pathophysiology

The fundamental pathologic change in meningococcemia is widespread vascular injury characterized by endothelial necrosis, intraluminal thrombosis, and perivascular hemorrhage. Endotoxin, cytokines, and free radicals damage the vascular endothelium, producing platelet deposition and vasculitis. The deleterious effects of cytokines play a major role in the pathogenesis of meningococcemia by causing severe hypotension, reduced cardiac output, and increased endothelial permeability.[8]

The clinical picture of meningococcemia is the product of compartmental intravascular infection and intracranial bacterial growth and inflammation. The pathogen binds tightly to the endothelial cells by type IV pili. From this arises microcolonies on the apical portion of the endothelial cell.[9] These bacteria invade the subarachnoid space with resultant meningitis in 50%-70% of cases. In a study by Brandtzaeg and van Deuren, of 862 patients, 37%-49% developed meningitis without shock, 10%-18% developed shock without meningitis, 7%-12% developed both, and 10%-18% with mild meningococcemia developed neither meningitis nor shock.[10]

Multiple organ failure, shock, and death may ensue as a result of anoxia in vital organs and massive disseminated intravascular coagulation (DIC).

Patients with fulminant meningococcemia develop thrombosis and hemorrhage in the skin, the mucous membranes, the serosal surfaces, the adrenal sinusoids, and the renal glomeruli. Adrenal hemorrhage is rarely extensive. Thrombosis of the glomerular capillaries may cause renal cortical necrosis, the chief characteristic of the generalized Shwartzman reaction. Thrombi containing numerous leukocytes are occasionally found in the lungs, and extensive intra-alveolar hemorrhage can occur. Myocarditis has been observed in adults with fatal meningococcal infections.

Virulence factors

Meningococci have 3 important virulence factors,[11] as follows:

  • Polysaccharide capsule - Individuals with immunity against meningococcal infections have bactericidal antibodies against cell wall antigens and capsular polysaccharide; a deficiency of circulating antimeningococcal antibodies is associated with disease.
  • Lipo-oligosaccharide endotoxin (LOS)
  • Immunoglobulin A1 (IgA1)

A polysaccharide capsule (which also determines the serogroup) enables the organism to resist phagocytosis.[8]

An LOS can be shed in large amounts by a process called blebbing, causing fever, shock, and other pathophysiology. This is considered the principal factor that produces the high endotoxin levels in meningococcal sepsis. Meningococcal LOS interacts with human cells, producing proinflammatory cytokines and chemokines, including interleukin 1 (IL-1), IL-6, and tumor necrosis factor (TNF). LOS is one of the important structures that mediate meningococcal attachment to and invasion into epithelial cells.[12]

LOS triggers the innate immune system by activating the Toll-like receptor 4MD2 cell surface receptor complex and myeloid in non-myeloid human sounds. The degree of activation of complement then coagulation system is directly related to the bacterial load.[13]

IgA1 protease cleaves lysosomal membrane glycoprotein-1 (LAMP1), helping the organism to survive intracellularly.

Septicemia

The clinical syndrome results from the activation and continued stimulation of the immune system by proinflammatory cytokines. This process is directly caused by bacterial components, such as endotoxins released from the bacterial cell wall, and is indirectly caused by the activation of inflammatory cells. The clinical spectrum of meningococcal septicemia is produced by 4 basic processes (ie, capillary leak, coagulopathy, metabolic derangement, myocardial failure). Combined, the processes produce multiorgan failure that usually causes cardiorespiratory depression and, possibly, renal, neurologic, and gastrointestinal (GI) failure.[14]

Capillary leak

From presentation until 2-4 days after illness onset, vascular permeability massively increases. Albumin and other plasma proteins leak into the intravascular space and urine, causing severe hypovolemia. This is initially compensated for by homeostatic mechanisms, including vasoconstriction. However, progression of the leak results in decreased venous return to the heart and a significantly reduced cardiac output.

Hypovolemia that is resistant to volume replacement is associated with increased mortality due to meningococcal sepsis. Children with severe disease often require fluid resuscitation involving volumes several times their blood volume in the first 24 hours of the illness, mostly in the first few hours. Pulmonary edema is common and occurs after 40-60 mL/kg of fluid has been given; it is treated with artificial ventilation.

Although capillary leak is the most important clinical event, the underlying pathophysiology is unclear. Some evidence suggests that meningococci and neutrophils cause the loss of negatively charged glycosaminoglycans, which are normally present on the endothelium. Also, the repulsive effect of albumin may be reduced in meningococcal infection; this change allows the protein leak. Albumin is normally confined to the vasculature because of its large size and negative charge, which repels the endothelial negative charge.

Coagulopathy

In meningococcemia, a severe bleeding tendency is often simultaneously present with severe thrombosis in the microvasculature of the skin, often in a glove-and-stocking distribution that can necessitate amputation of digits or limbs. Clinicians face a dilemma because supplying platelets, coagulation factors, and fibrinogen may worsen the process. Meningococcal infection affects the main pathways of coagulation.

Endothelial injury results in platelet-release reactions. Along with stagnant circulation due to local vasoconstriction, platelet plugs form to start the process of intravascular thrombosis. In the plasma, soluble coagulation factors are consumed, and the natural inhibitors of coagulation (eg, the tissue factor pathway inhibitor antithrombin III) are down-regulated; this process further encourages thrombosis.

The protein C pathway probably plays a key role in the pathogenesis of purpura fulminans. A very similar rash occurs in neonates with congenital protein C deficiency and in older children who develop antibodies to protein S following varicella infection. Many patients with meningococcal infection are unable to activate protein C in the microvasculature due to endothelial downregulation of thrombomodulin.[15] Protein C and S levels are low in children with meningococcal disease. However, low levels may occur in patients with septic shock without purpura fulminans. Plasma anticoagulants (tissue factor pathway inhibitor and antithrombin) are also down-regulated in meningococcal sepsis.

The fibrinolytic system in meningococcal disease is down-regulated as well, reducing plasmin generation and removing an aspect of endogenous negative feedback to clot formation. In addition, plasminogen activator inhibitor levels are dramatically increased, further reducing the efficacy of the endogenous tissue plasminogen activator.

Metabolic derangement

Severe electrolyte abnormalities, including hypokalemia, hypocalcemia, hypomagnesemia, and hypophosphatemia, may occur in the setting of severe acidosis. 

Myocardial failure

Myocardial function remains impaired even after circulating blood volume is restored and metabolic abnormalities are corrected. Reduced ejection fractions and elevated plasma troponin I levels indicate myocardial damage. A gallop rhythm is often audible, with elevated central venous pressure and hepatomegaly. Hemodynamic studies in patients with meningococcal sepsis have shown that the severity of disease is related to the degree of myocardial dysfunction.

Myocardial failure in meningococcal sepsis is undoubtedly multifactorial, but various proinflammatory mediators (eg, nitric oxide, TNF-alpha, IL-1B) released in sepsis appear to have a direct negative inotropic effect on the heart, depressing myocardial function. A study using new microarray technology showed that IL-6 is the key factor that causes myocardial depression in meningococcemia.[16, 17]

Other factors that reduce myocardial function, such as acidosis, hypoxia, hypoglycemia and electrolyte disturbances, are all common in severe meningococcal disease.

Meningitis

Meningococcal meningitis generally has a better prognosis than septicemia. After bacteria enter the meninges, they multiply in the CSF and pia arachnoid. In the early stages of infection, the tight junctions between the endothelial cells that form the blood-brain barrier isolate the CSF from the immune system; this isolation allows bacterial multiplication. Eventually, inflammatory cells enter the CSF and release cytokines that play a central role in the pathophysiology of meningeal inflammation.[14, 1]

Neurologic damage is a consequence of the following 3 main processes:

  • Direct bacterial toxicity
  • Indirect inflammatory processes, such as cytokine release, ischemia, vasculitis, and edema
  • Systemic effects, including shock, seizures, and cerebral hypoperfusion

Cerebral edema may be caused by increased secretion of CSF, diminished reabsorption of CSF, and/or breakdown of the blood-brain barrier. Obstructive hydrocephalus may cause increased accumulation of CSF between cells.

Increased ICP secondary to cerebral edema, loss of cerebrovascular autoregulation, and reduced arterial perfusion pressure secondary to shock reduce cerebral blood flow in bacterial meningitis. Reduced cerebral blood flow with vasculitis and thrombosis of cerebral vessels may cause ischemia and neuronal injury.

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Etiology

N meningitidis is a gram-negative diplococcus (see the image below) that grows well on solid media supplemented with blood and incubated in a moist atmosphere enriched with carbon dioxide.

Gram-negative intracellular diplococci. Courtesy P Gram-negative intracellular diplococci. Courtesy Professor Chien Liu.

Oxidase and catalase are biochemical markers for preliminary identification of N meningitidis. Sugar fermentations are required for final identification of the species. N meningitidis ferments glucose and maltose but not sucrose or lactose.

Agglutination reactions with immune serum are used to segregate meningococci into 13 serogroups: A, B, C, D, X, Y, Z, E, W-135, H, I, K, and L, depending on the group-specific capsular polysaccharide antigen. Ninety-eight percent of infections are caused by encapsulated serogroups A, B, C, Y, and W-135, although of these groups, A, B, and C occur most frequently in meningococcal disease. The cell wall of pathogenic meningococci contains a toxic lipopolysaccharide or endotoxin that is chemically identical to enteric bacilli endotoxin.

Transmission

The human nasopharynx is the only known reservoir for N meningitidis. The organism is transmitted via aerosols and nasopharyngeal secretions. Meningococcal infection is preceded by nasopharyngeal colonization. Attachment to the nasopharyngeal epithelial cells is aided by meningococci-expressed pili, such as the type IV pilus encoded by pilC, which binds to human cell surface protein CD46.

Meningococci then enter the bloodstream and spread to specific sites, such as the meninges or joints, or disseminate throughout the body. Five percent of individuals become long-term carriers, most of whom are asymptomatic. In outbreaks, the carriage rate of an epidemic strain can reach 90%. The likelihood of acquiring infection is increased 100-1000 times in intimate contacts of individuals with meningococcemia.

A study of 14,000 teenagers in the United Kingdom found that attendance at pubs or clubs, intimate kissing, and cigarette smoking were each independently and strongly associated with an increased risk of meningococcal carriage.[18]

Immunity

Passively transferred maternal antibody provides temporary protection to infants for the first 3-6 months of life. As the child grows older, asymptomatic exposure to a variety of encapsulated and nonencapsulated N meningitidis strains increases protective bacterial immunity. Most individuals acquire immunity to meningococcal disease by age 20 years; protective IgM and IgG are found in up to 95% of young adults.

An episode of meningococcal disease confers group-specific immunity, but a second episode may be caused by another meningococcal serogroup.

Susceptibility

Complement deficiency

A genetic component to host susceptibility to meningococcemia is becoming more established. IgG antibodies that have specificity for meningococcal polysaccharides mediate bactericidal activity. Complement is needed for expression of this activity. Terminal complement deficiency is well known to predispose individuals to meningococcemia.

Genetic variants of mannose-binding lectin, a plasma opsonin that initiates another pathway of complement activation, may account for nearly one third of the cases of invasive meningococcal disease.

Meningococcemia is particularly common among individuals with deficiencies of terminal complement components C5-C9 or properdin. These late complement components are required for bacteriolysis of meningococci.

An estimated 50-60% of individuals with late complement component deficiencies develop at least 1 episode of meningococcal disease. Many of these patients experience multiple episodes of infection.

Acquired complement deficiencies that occur in association with systemic lupus erythematosus, multiple myeloma, severe liver disease, enteropathies, and nephrotic syndrome also predispose to meningococcal infection.

Interleukin abnormalities

Specific genetic polymorphisms are likely to predispose individuals to mortality in severe sepsis. An association has been described between increased risk of mortality in children with meningococcal disease and polymorphisms in the IL-1 cluster.

An innate anti-inflammatory cytokine profile (low level of TNF and high level of IL-10) is also associated with fatal meningococcal disease.

Coagulation pathway abnormalities

Polymorphisms in the genes that control the coagulation pathways are being evaluated. Patients with the prothrombotic factor V Leiden mutation are at higher risk for thrombotic complications, such as amputations and skin grafting, but do not have increased mortality in meningococcemia.

Other

An increased type-1 plasminogen activator inhibitor response to TNF meningococcal septicemia has been demonstrated to result from a polymorphism in the PAI-1 gene.

Another study reported that a toll-like receptor 4 variant genotype was associated with increased mortality in children with invasive meningococcal disease.[19]

Risk factors

Most patients with meningococcal disease were previously healthy; however, patients with certain medical conditions are at increased risk for developing meningococcal infection. Risk factors include the following:

  • Close contact with a patient with primary invasive disease: Epidemics among new recruits (eg, in "Boot Camp") and college freshmen in dormitories are classic examples of meningococcal spread and (see Epidemiology).
  • Recent viral respiratory illness (eg, influenza): A study showed increased rates of meningococcal disease in children during periods of increased influenza and respiratory syncytial virus activity. [20]
  • Smoking or exposure to secondary smoke
  • Host susceptibility: Individuals with deficiency of complement components C5-C9 and abnormal complement factor H [21]
  • Socioeconomic deprivation
  • Household overcrowding
  • Individuals with HIV infection (see Epidemiology)

Patients with anatomic or functional asplenia are also at increased risk for invasive meningococcal disease.

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Epidemiology

Occurrence in the United States

Although endemic in North America, meningococcal infections follow a pattern of multiyear cycles. The most recent peak occurred in 1996 (1.1 cases/100,000 population). In contrast, the incidence in 2005 was 0.4 cases/100,000 population. This decline began before the use of conjugate vaccine among adolescents in 2005..[22] By 2011, the incidence had decreased to 0.3 cases/100,000 population.[23] In 2006, 1194 cases of meningococcal disease were reported in the United States; 974 cases were reported in 2007.[24, 25]

Outbreaks account for less than 5% of meningococcal infections in the United States. They may be restricted to a closed population or may involve a larger community. In a Los Angeles County outbreak of meningococcal disease, nearly one half of community residents with the disease had had contact with persons who had been incarcerated.[26]

The increased risk of invasive meningococcal disease among young adults who live in close quarters under stressful situations has been long recognized. The prototype of this type of outbreak is that among military recruits living in crowded barracks. Resultant disruption and basic training prompted the Department of Defense to initiate development of the original meningococcal vaccines.[27]

Between 2010 and March 2013, 22 cases of meningococcal infection, serogroup C, were documented in New York City among men who have sex with men (MSM). Sixteen of these occurred in 2013. Fifty percent involved blacks. Fifty-five percent of infected persons were also HIV-positive. Seven cases were fatal.

In 2012, the incidence of meningococcal disease among MSM aged 18-64 years in New York City was 12.6 per 1000 population, compared with 0.16 per 500,000 non-MSM population. In 2014, there were 4 additional cases. Several outbreaks were reported in Los Angeles during the same time.[28]

In the HAART era, the relative risk of meningococcal disease among persons with HIV infection was 10, with the greatest likelihood among those with CD4 counts less than 200/µL.[29]

The incidence of meningococcal infection among healthcare workers and first responders is quite low. However, it is estimated that the rate of acquisition of meningococcal by microbiological laboratory workers infection in the United States is significant. The vast majority of cases were associated with absence of any respiratory protection during the time that the specimens were handled.[30]

Thirty-five percent of meningococcal disease cases are caused by serogroup C, 32% by serogroup B, and 26% by serogroup Y.[31] Since 2005, the year that the quadrivalent (serogroup A, C, W-135, and Y) conjugated meningococcal vaccine was made available, there has been a rise in outbreaks of serogroup B infection on college campuses.[32]

Patients with complement deficiencies have a higher proportion of meningococcal disease caused by serotypes Y and W-135.

International occurrence

Serogroups A, B, and C account for most cases of meningococcal disease worldwide. Serogroups A and C predominate in Asia and Africa, while serogroups B and C predominate in Europe, North America, and South America.

An international outbreak of meningococcal disease associated with serogroup W-135 occurred following the return of travelers who participated in the annual hajj (pilgrimage) to Mecca, in Saudi Arabia, in 2000 and 2001.[33, 34, 35]

Outbreaks have also occurred in Africa, parts of Asia, South America, and the former Soviet republics. Serogroup A is usually implicated in these epidemics. Indeed, for more than a century, serogroup A meningococcal disease has been endemic in the African Meningitis Belt (see the map below), which extends from Ethiopia in eastern Africa to Senegal in West Africa. Large-scale outbreaks occur at cyclic intervals of 7-10 years through these central African countries, with attack rates as high as 400-500 cases per 100,000 population.[36]

Areas with frequent epidemics of meningococcal dis Areas with frequent epidemics of meningococcal disease. This is known as the Meningitis Belt of Africa; visitors to these locales may benefit from meningitis vaccine. Image courtesy of CDC.

Meningococcal disease may also be a significant, but underreported, problem in developing Asian countries.[37]

Europe and the United Kingdom

Approximately 1500 laboratory-confirmed cases of meningococcal infection occur each year in the United Kingdom. More specifically, 1303 confirmed cases were reported in 2006, and 1283 cases were reported in 2007. However, a total of as many as 5000 cases of meningococcal infection are believed to occur in the United Kingdom annually.[38, 39]

Data from 1995 showed that strains in serogroup B caused as many as 70% of cases in the United Kingdom and that strains in group C caused 30-40% of cases. However, introduction of the serogroup C vaccine in 1999 resulted in a significant reduction in the rates of meningococcal disease in the United Kingdom, because serogroup C disease was virtually eliminated.[38]

Currently, serogroup B still accounts for most cases of meningococcal disease in the United Kingdom (87% from 2004-2007), although a few cases of disease caused by strains in serogroups Y and W-135 have been reported. In addition, a small number of cases caused by serogroup C are still reported; these accounted for approximately 2.5-3% of all confirmed cases of meningococcal disease in 2006-2007.[39]

Climate-related demographics

Meningococcal infections in the United States and Northern Europe are most common in the winter, while cases of meningococcal disease in the African Meningitis Belt increase at the end of the dry season.

Race- and sex-related demographics

One population-based study in the United States found that the incidence of meningococcal disease was significantly higher among African Americans (1.5 cases per 100,000 population) than among Anglo-Americans (1.1 cases per 100,000 population). The disease is also higher in lower socioeconomic groups in the United States.

Meningococcal disease is somewhat more prevalent in males (1.2 cases per 100,000) than in females (1 case per 100,000).

Age-related demographics

In epidemics of meningococcal disease, people of any age may be affected, with the case distribution shifted toward older individuals.[40]

Endemic meningococcal disease is most common in children aged 6-36 months. Children younger than 6 months are protected by maternal antibodies, (although occult meningococcemia, an uncommon form of infection, affects children aged 3-24 months). (See the image below.)

Lesions caused by Neisseria meningitis bacteremia Lesions caused by Neisseria meningitis bacteremia on the palm of the hand of a 9-month-old infant. Photo by D. Scott Smith, MD, taken at Stanford University Hospital.

A second, less dramatic peak in incidence occurs among teenagers and college students; this may be due to changes in social behavior and increases in close interpersonal contact in these populations. About one third of meningococcal disease cases occur in adults.

In New York City, from 1989-2000, the overall incidence rates of meningococcal disease decreased. The median age of patients with meningococcal disease increased from 15 years in 1989-1991 to 30 years in 1998-2000.[41]

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Prognosis

Meningococcal disease can progress very quickly and can result in loss of life, neurologic impairment, or peripheral gangrene. Patients with terminal complement component deficiency have a more favorable prognosis. A fatal outcome is highly associated with properdin deficiencies. Coagulopathy with a partial thromboplastin time of greater than 50 seconds or a fibrinogen concentration of less than 150 µg/dL are also markers of poor prognosis.

A multicenter study evaluating the serogroups in children with N meningitis infection found that meningococcal disease continues to result in substantial morbidity and mortality in children. The study found that, overall, 55 (44%) of isolates were serogroup B, 32 (26%) were serogroup C, and 27 (22%) were serogroup Y. All but 1 isolate (intermediate) were susceptible to penicillin. The overall mortality rate in this pediatric population was 8%.[42]

Cases of meningococcal meningitis without coma or focal neurological deficits have markedly better outcomes. Most of these patients recover completely when appropriate antimicrobial therapy is administered promptly upon presentation.

Isolated meningococcal meningitis (5% mortality rate) has a better prognosis than meningococcal septicemia (10%-40% mortality rate).

Patients with higher bacterial loads on polymerase chain reaction (PCR) testing are more likely to die or have permanent disease sequelae and experience longer hospital stays.[43]

Morbidity

Complications of meningococcal infection include the following:

  • DIC
  • Vasomotor collapse and shock
  • Adrenal hemorrhage and insufficiency
  • Cranial nerve dysfunction, particularly involving the sixth, seventh, and eighth cranial nerves
  • Seizures or deafness in the acute stages of meningitis
  • Postmeningitic epilepsy (rare)
  • Coma
  • Thrombocytopenia
  • Herpes labialis (5%-20% of patients with meningococcal disease)
  • Immune complex arthritis involving multiple joints
  • Pericarditis due to immunologic reaction or toxin
  • Cardiorespiratory failure that requires tracheal intubation and inotropic support
  • Renal failure that requires hemofiltration, hemodialysis, or peritoneal dialysis
  • Peritoneal compartment syndrome due to severe abdominal capillary leak that requires placement of a tap
  • Psychological disturbance after intensive care or complications
  • Tamponade due to pericarditis
  • Gangrene
  • Osteomyelitis
  • Purulent conjunctivitis and sinusitis

Complications of meningococcemia may occur at the time of acute disease or during the recovery phase. Patients with fulminant meningococcemia may develop respiratory insufficiency and require mechanical ventilation. Those with severe DIC may bleed into their lungs, urinary tract, and gastrointestinal tract. Ischemic complications of DIC have been reported in up to 50% of survivors of fulminant meningococcemia.

Complications of meningococcal infection include immune complex disease leading to arthritis, pericarditis, myocarditis, and pneumonitis 10-14 days after the primary infection. Up to 5% of patients with meningococcemia develop a nonpurulent pericarditis with substernal chest pain and dyspnea approximately 1 week after the onset of illness. Involvement of the pericardium in meningococcal disease is a well-recognized, but rare, complication. It has been described with N meningitidis serotypes C, B, W-135, and Y.[44]

Meningococcal meningitis may progress to mental obtundation, stupor, or coma, which may be related to increased ICP, and such patients are prone to herniation. Other rare complications of meningitis include acute and delayed venous thrombosis, which usually manifests as a focal neurologic deficit.

Meningococcal infection may spread through the bloodstream and localize in other parts of the body, where it can cause suppurative complications. Septic arthritis, purulent pericarditis,[45] and endophthalmitis[46] can occur but are uncommon.

Meningococcal pneumonia has been described and probably results from aspiration of N meningitidis. The W-135 serogroup of meningococci was found to be more likely to cause this form of meningococcal disease, as well as pericarditis and septic arthritis.

Approximately 10% of patients with meningococcal disease develop nonsuppurative arthritis, usually of the knee joints. The nonsuppurative arthritis of meningococcal disease may result from tenosynovitis due to meningococcemia or a postinfectious immunologic process.

Recurrent meningococcal disease has been associated with hereditary deficiencies of various terminal components of the complement system.

Sequelae

A case-control study examined outcomes in patients who had survived meningococcal disease in adolescence and found that they had poorer mental health, social support, quality of life, and educational outcomes, as well as greater fatigue, than did well-matched controls.[47]

A European study found that approximately 4% of survivors of meningococcal infection had sequelae. In the United Kingdom, approximately 5% of survivors have neurologic sequelae, mainly sensorineural deafness. Amputation or skin grafting due to digital or limb ischemia and severe skin necrosis is required in 2-5% of survivors in the United Kingdom.

In the United States in 2005, 11-19% of survivors of meningococcal infection had serious health sequelae, including sensorineural hearing loss, amputations, and cognitive impairment.

A study from the Netherlands involving patients who had survived meningococcal septic shock in childhood found that 35% of these patients had some degree of neurologic impairment; chronic headache accounted for the largest proportion of impairment symptoms.[48]

Another study from the Netherlands examined skin scarring and orthopedic sequelae following meningococcal septic shock. Forty-eight percent of children had skin scarring, ranging from extremely disfiguring scars to those that were barely visible; 14% of patients had orthopedic sequelae; 8% had undergone amputation; and 6% had lower limb length discrepancy (more common in patients who were particularly young when admitted to the pediatric intensive care unit [PICU] for meningococcal septic shock). Patients with scars or orthopedic sequelae had significantly higher illness severity scores. (See the images below.)[49]

A 9-month-old baby in septic shock with purpuric N A 9-month-old baby in septic shock with purpuric Neisseria meningitis skin lesions. Photo by D. Scott Smith, MD, taken at Stanford University Hospital.
The leg of a 9-month-old infant in septic shock wi The leg of a 9-month-old infant in septic shock with a rapidly evolving purpuric rash. Photo by D. Scott Smith, MD, taken at Stanford University Hospital.
Neisseria meningitis purpuric lesions on the ear a Neisseria meningitis purpuric lesions on the ear and cheek of a 9-month-old infant who is in septic shock. Photo by D. Scott Smith, MD, taken at Stanford University Hospital.

Mortality

The case-fatality rate of meningococcal infections varies depending on the prevalence of disease, the clinical form of disease, and the socioeconomic conditions of the society in which the infections occur. In the United States, the case-fatality rate is approximately 10%.

Specialty units in geographic areas with a high incidence of meningococcal infections have reduced their mortality rates to less than 5%.

The prognosis of fulminant meningococcemia is guarded. Approximately one half of patients who present with this form of meningococcal disease do not survive, even with prompt administration of appropriate antimicrobial therapy. Most deaths occur within 48 hours. The mortality rate can be as high as 70% in developing countries. Survivors of fulminant meningococcemia may have ischemic complications.

Cases of fulminant meningococcemia can also be associated with the complication of massive adrenal hemorrhage (Waterhouse-Friderichsen syndrome). In these cases, the mortality rate is close to 100%.

A mortality rate of 40-80% in patients with meningococcemia is associated with the acute onset of petechiae less than 12 hours before admission, shock, coma, high fever, low peripheral leukocyte count, thrombocytopenia, high serum antigen titer, absence of meningitis, metabolic acidosis, and DIC. Half of all patients with shock who die do so within the first 12 hours of hospitalization.[50] Meningococcemia associated with DIC has a mortality rate of higher than 90%.

Isolated meningococcal meningitis (5% mortality rate) has a better prognosis than meningococcal septicemia (10-40% mortality rate). In 2005, the mortality rate in the United States was 10-14%. Meningococcal meningitis without antibiotic therapy is uniformly fatal.

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Patient Education

Health education improves public recognition of nonblanching rashes associated with meningococcal disease and was instrumental in reducing mortality in the United Kingdom.

Parents readily recognize the tumbler test; if a rash does not fade when a glass tumbler is pressed against the skin, the rash is nonblanching, and medical advice should be sought immediately.

Further information is available from the charities and patient-support organizations such as the Meningitis Research Foundation (MRF) and The National Meningitis Trust.

For patient education information, see the Children's Health Center, the Brain and Nervous System Center, and the Infections Center, as well as Meningitis in Adults, Meningitis in Children, and Brain Infection.

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Contributor Information and Disclosures
Author

Mahmud H Javid, MBBS Consultant in Infectious Diseases, Shifa International Hospital, Pakistan

Mahmud H Javid, MBBS is a member of the following medical societies: Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Coauthor(s)

Shadab Hussain Ahmed, MD, AAHIVS, FACP, FIDSA Professor of Clinical Medicine, The School of Medicine at Stony Brook University Medical Center; Adjunct Clinical Associate Professor, Department of Medicine, New York College of Osteopathic Medicine of New York Institute of Technology; Attending Physician, Department of Medicine, Division of Infectious Diseases, Director of HIV Prevention Services, Administrative HIV Designee, Nassau University Medical Center

Shadab Hussain Ahmed, MD, AAHIVS, FACP, FIDSA is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

John L Brusch, MD, FACP Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance

John L Brusch, MD, FACP is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Acknowledgements

Katrina Cathie, BM (Hons), MRCPCH,  Fellow in Paediatric Clinical Research, Southampton NIHR Respiratory Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust, UKKatrina Cathie, BM(Hons), MRCPCH is a member of the following medical societies: Royal College of Paediatrics and Child Health

Disclosure: Nothing to disclose.

Joanna L Chan, MD Mohs Fellow, California Skin Institute

Joanna L Chan, MD is a member of the following medical societies: American Academy of Dermatology and American Society for Dermatologic Surgery

Disclosure: Nothing to disclose.

Joseph Domachowske, MD Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University

Joseph Domachowske, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Saul N Faust, MA, MBBS, PhD, MRCPCH Senior Lecturer in Pediatric Immunology and Infectious Diseases, University of Southampton; Director, Wellcome Trust Clinical Research Facility, Southampton University Hospitals NHS Trust, UK

Saul N Faust, MA, MBBS, PhD, MRCPCH is a member of the following medical societies: British Paediatric Allergy, Immunology and Infectious Group, European Society for Paediatric Infectious Diseases, International Society for Infectious Diseases, and Royal College of Paediatrics and Child Health

Disclosure: Xoma Consulting fee Consulting; GSK Honoraria Consulting; Wyeth travel and registration fee to conference investigator in study being presented at meeting; Sanofi Pasteur Consulting fee Consulting; Pfizer Consulting fee Consulting

Aaron Glatt, MD Professor of Clinical Medicine, New York Medical College; President and CEO, Former Chief Medical Officer, Departments of Medicine and Infectious Diseases, St Joseph Hospital (formerly New Island Hospital)

Aaron Glatt, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society for Microbiology, American Thoracic Society, American Venereal Disease Association, Infectious Diseases Society of America, International AIDS Society, and SocietyforHealthcareEpidemiology of America

Disclosure: Nothing to disclose.

Thomas A Hoffman, MD Professor, Department of Internal Medicine, Division of Infectious Diseases, Jackson Memorial Hospital, University of Miami

Thomas A Hoffman, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

David Jaimovich, MD Chief Medical Officer, Joint Commission International and Joint Commission Resources

David Jaimovich, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Michael Levin, PhD, FRCP, FRCPCH Head, Professor, Imperial College School of Medicine at St Mary's Hospital, Department of Pediatrics, London, England

Disclosure: Nothing to disclose.

Lester F Libow, MD Dermatopathologist, South Texas Dermatopathology Laboratory

Lester F Libow, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Texas Medical Association

Disclosure: Nothing to disclose.

Joseph Richard Masci, MD Professor of Medicine, Professor of Preventive Medicine, Mount Sinai School of Medicine; Director of Medicine, Elmhurst Hospital Center

Joseph Richard Masci, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, Association of Professors of Medicine, and Royal Society of Medicine

Disclosure: Nothing to disclose.

Mary D Nettleman, MD, MS, MACP Professor and Chair, Department of Medicine, Michigan State University College of Human Medicine

Mary D Nettleman, MD, MS, MACP is a member of the following medical societies: American College of Physicians, Association of Professors of Medicine, Central Society for Clinical Research, Infectious Diseases Society of America, and Society of General Internal Medicine

Disclosure: Nothing to disclose.

Gregory J Raugi, MD, PhD Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle School of Medicine; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle

Gregory J Raugi, MD, PhD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Nanette Silverberg, MD Assistant Clinical Professor, Department of Dermatology, Columbia University College of Physicians and Surgeons; Director of Pediatric Dermatology, Department of Dermatology, St Luke's Roosevelt Hospital Center, Maimonides Medical Center and Beth Israel Medical Center

Nanette Silverberg is a member of the following medical societies: American Academy of Dermatology, American Academy of Pediatrics, American Association of University Women, American Medical Association, American Medical Women's Association, Dermatology Foundation, International Society of Pediatric Dermatology, Phi Beta Kappa, Sigma Xi, Society for Pediatric Dermatology, and Women's Dermatologic Society

Disclosure: Nothing to disclose.

Darvin Scott Smith, MD, MSc, DTM&H Adjunct Assistant Professor, Department of Microbiology and Immunology, Stanford University School of Medicine; Chief of Infectious Diseases and Geographic Medicine, Department of Internal Medicine, Kaiser Redwood City Hospital

Darvin Scott Smith, MD, MSc, DTM&H is a member of the following medical societies: American Medical Association, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, and International Society of Travel Medicine

Disclosure: Nothing to disclose.

Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Elizabeth L Tanzi, MD Co-Director, Laser Surgery, Washington Institute of Dermatologic Laser Surgery; Assistant Professor, Department of Dermatology, Johns Hopkins University School of Medicine

Elizabeth L Tanzi, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, and American Society for Laser Medicine and Surgery

Disclosure: Nothing to disclose.

Michael J Wells, MD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Dorsum of the hand showing petechiae. Courtesy of Professor Chien Liu.
Petechiae on the palm. Courtesy of Professor Chien Liu.
Petechiae on lower extremities. Courtesy of Professor Chien Liu.
Conjunctival petechiae. Courtesy of Professor Chien Liu.
Gram-negative intracellular diplococci. Courtesy Professor Chien Liu.
Scattered petechiae in a patient with acute meningococcemia.
Purpura in a young adult with fulminant meningococcemia.
The legs of a 22-year-old woman in septic shock with a rapidly evolving purpuric rash. Photo by D. Scott Smith, MD, taken at Stanford University Hospital.
A 9-month-old baby in septic shock with purpuric Neisseria meningitis skin lesions. Photo by D. Scott Smith, MD, taken at Stanford University Hospital.
The leg of a 9-month-old infant in septic shock with a rapidly evolving purpuric rash. Photo by D. Scott Smith, MD, taken at Stanford University Hospital.
Neisseria meningitis purpuric lesions on the ear and cheek of a 9-month-old infant who is in septic shock. Photo by D. Scott Smith, MD, taken at Stanford University Hospital.
Lesions caused by Neisseria meningitis bacteremia on the palm of the hand of a 9-month-old infant. Photo by D. Scott Smith, MD, taken at Stanford University Hospital.
Areas with frequent epidemics of meningococcal disease. This is known as the Meningitis Belt of Africa; visitors to these locales may benefit from meningitis vaccine. Image courtesy of CDC.
Child with severe meningococcal disease and purpura fulminans.
Flow chart shows guidelines for the emergency management of meningococcal disease in children. These guidelines may be reprinted for use in clinical areas and are available at Meningitis.org.
Flow chart shows guidelines for the emergency management of meningococcal disease in adult patients. These guidelines may be reprinted for use in clinical areas and are available from Meningitis.org.
Chart for family practice recognition and management of meningococcal disease (courtesy of Meningitis.org).
 
 
 
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