eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease
Meningococcal Infections
Updated: Sep 11, 2009
Introduction
Background
The gram-negative diplococcus Neisseria meningitides is a major infectious cause of childhood death in developed countries. The mortality rate remains around 10%; however, in some specialist centers, it has decreased to less than 5%.1
Only meningitis is present in 30-50% of cases of invasive meningococcal disease, whereas 7-10% of cases have only features of septicemia, and 40% have meningitis with septicemia. The clinical difference between septicemia and meningitis is important because patients who present with shock are treated differently than patients who present primarily with increased intracranial pressure (ICP).
Child with severe meningococcal disease and purpura fulminans.
Pathophysiology
Transmission is person-to-person by direct contact through infected droplets of respiratory secretions, often from asymptomatic carriers. In terms of transmission and immunity, as many as 30% of teenagers and 10% of adults carry meningococci in their upper respiratory tracts at any given time, although pathogenic strains are found in only 1% of carriers. Immunity to N meningitidis is probably acquired through intermittent nasal carriage of meningococci and antigenic cross-reaction with enteric flora during the first 2 decades of life. Disease usually occurs sooner than 10 days after a pathogenic strain penetrates the nasopharyngeal mucosa in a susceptible individual and can survive in the blood stream. Disease may involve septicemia, meningitis, or both.2
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, neurological, and GI failure.2
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 by homeostatic mechanisms, including vasoconstriction. However, as the leak progresses, this 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 that 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 following 3 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 downregulated; this process further encourages thrombosis.
- The protein C pathway is thought to be crucial in the development of purpura fulminans because a similar purpuric rash is seen in neonates with congenital protein C deficiency and in older children who develop antibodies to protein S after varicella infection. Protein C is a vitamin K–dependent plasma protein that is in an inactive form in the plasma. When it is activated (by binding with the thrombin-thrombomodulin complex), it has anticoagulant functions (using protein S as a cofactor). Many patients appear to be unable to activate protein C in the microvasculature due to endothelial downregulation of thrombomodulin.3 Protein C and S levels are low in children with meningococcal disease, but similar levels are observed in patients with septic shock, whether or not a severe rash develops. The mechanisms by which severe purpura develops in some children but not others are currently under investigation.
- Plasma anticoagulants (tissue factor pathway inhibitor and antithrombin) are also downregulated in meningococcal sepsis.
- The fibrinolytic system is also downregulated in meningococcal disease, 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. Despite previous case reports, recombinant tissue plasminogen activator is no longer used in severe purpura fulminans because of a high incidence of intracranial hemorrhage in a retrospective series with no control group.
Metabolic derangement
Profound acidosis occurs with severe metabolic abnormalities (which occur paradoxically in the presence of acidosis), including hypokalemia, hypocalcemia, hypomagnesemia, and hypophosphatemia.
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, tumor necrosis factor alpha, interleukin [IL]-1B) released in sepsis appear to have a direct negative inotropic effect on the heart, depressing myocardial function. A recent study using new microarray technology has shown that IL-6 is the key factor that causes myocardial depression in meningococcemia.4,5 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 cerebrospinal fluid (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.2,6
Neurological 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.
Frequency
United States
Meningococcal infections are most common in the winter and are relatively rare in North America. Invasive disease (meningitis and sepsis) occurred in 0.5 individuals per 100,000 inhabitants in the United States in 2005. In 2006, 1194 cases were reported in the United States, and 974 cases were reported in 2007.7 From 1992-1996, 32% of strains isolated in the United States were attributed to the group B serotype, 35% were in group C, and 26% were in group Y. A vaccine with immunogenicity against A, C, Y, and W135 became available in the United States in 2006 and is recommended for all children older than 11 years.
International
As in the United States, meningococcal infections are most common in the winter in Northern Europe. In the United Kingdom in 2004, the incidence was 7.5 cases per 100,000 population (aged <20 y). Approximately 1500 laboratory-confirmed cases occur each year in the United Kingdom; however, as many as 5000 cases are believed to occur in total. In the United Kingdom, 1303 confirmed cases were reported in 2006, and 1283 cases were reported in 2007.8
Data from 1995 showed that strains in serogroup B caused as many as 70% of cases, and strains in group C caused 30-40% of cases. Other serogroups (ie, Y and W135) accounted for a few cases each year. Introduction of the serogroup C vaccine in 1999 resulted in a significant reduction in the rates of meningococcal disease because serogroup C disease was virtually eliminated. In the United Kingdom, most cases are now caused by strains in serogroup B; however, a few cases of disease caused by strains in serogroups Y and W135 have been reported. Serogroup C disease cases are still reported; approximately 2.5-3% of all confirmed cases in 2006-2007 were serogroup C. From 2004-2007, 87% of meningococcal cases in the United Kingdom were caused by strains in serogroup B.8
The quadrivalent ACYW vaccine may soon be available in Europe; however, without a vaccine for serogroup B, the incidence of disease is unlikely to significantly decline. In the "meningitis belt" of sub-Saharan Africa, the incidence increases at the end of the dry season. Strains in serogroup A are mainly responsible for epidemics in the "tropical meningitis belt."
Mortality/Morbidity
- 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%.
- Specialty units in geographical areas with a high incidence of meningococcal infections have reduced their mortality rates to less than 5%.
- In a recent European study, approximately 4% of survivors had sequelae.
- In the United Kingdom, approximately 5% of survivors have neurological 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 States in 2005, 11-19% of survivors had serious health sequelae, including sensorineural hearing loss, amputations, and cognitive impairment.
Race
For unexplained reasons, the prevalence rate in the United States is higher among blacks (1.5 cases per 100,000 persons) than in whites (1.1 cases per 100,000 persons).
Sex
Invasive infection is slightly more common in males than in females. The ratio is highest in infancy and gradually decreases with age.
Age
- Infection with N meningitides is highest in children aged 6 months to 2 years; these children have lost the maternal antibody and have not yet developed mature humoral immunity.
- Increased infection rates in infancy may be because of low innate levels of bactericidal permeability increasing protein, which is a protective neutrophil protein.
- A second and less dramatic peak occurs among teenagers and college students and perhaps is due to a change in social behavior and an increase in close interpersonal contact.
Clinical
History
- Meningitis is associated with the following:6
- Headache
- Fever
- Vomiting
- Photophobia
- Lethargy
- Neck stiffness
- Rash in more than 50% of cases
- Seizures in 20% of patients at presentation and in an additional 10% of patients within 72 hours
- Early nonspecific symptoms, especially in infants
- Septicemia may be confused with influenza, particularly when myalgia is prominent. Meningococcal septicemia is characterized by the following:9
- Fever
- Rash (may initially be erythematous and may change to petechiae and purpura)
- Vomiting
- Headache
- Myalgia
- Abdominal pain
- Tachycardia/tachypnea
- Hypotension
- Cool extremities
- Initially normal level of consciousness
- Early symptoms indistinguishable from those associated with viral illness, including leg pain
- Symptoms of meningitis and septicemia may occur together and may complicate the distinction between the acute depression in level of consciousness due to hypotension and that due to elevated ICP.
Physical
Physical examination may reveal the following findings:
- Although early infection is often associated with a maculopapular rash, a nonblanching rash (petechial or purpuric) subsequently develops in 80% of children. A maculopapular rash remains in 13% of children, and no rash occurs in 7%.
- The clinical signs of meningitis, such as neck stiffness and photophobia, and a positive Kernig sign are not present in all cases. These signs are often absent in infants. A rapid decrease in the level of consciousness, focal neurological deficits, coma, bradycardia, hypertension, asymmetric pupils, and decerebrate posturing indicate increased ICP. Rarely, the child can present with meningoencephalitis with elevated ICP and rapidly deteriorating neurological findings, which may lead to coning and death.
- Fever, rash, tachycardia, hypotension, cool extremities, and an initially normal level of consciousness indicate meningococcal septicemia.
- The disease may progress in only a few hours.
- Confusion, cold extremities, poor capillary refill, and increasing tachycardia may herald a precipitous decrease in blood pressure.
- An increasing respiratory rate suggests pulmonary edema or shock. Generalized edema develops as a result of capillary leak syndrome, and myocardial depression further impairs tissue perfusion.
Causes
Risk factors and genetic components for meningococcal infections have been identified.
- Risk factors include the following:
- Close contact with a patient with primary invasive disease
- Recent viral respiratory illness (eg, influenza): A recent study showed increased rates of meningococcal disease in children during periods of increased influenza and respiratory syncytial virus activity.10
- Smoking or exposure to secondary smoke
- Host susceptibility
- Socioeconomic deprivation
- Household overcrowding
- A genetic component to host susceptibility is becoming clearer. Terminal complement deficiency is well known to predispose individuals to meningococcemia. Specific genetic polymorphisms are likely to predispose individuals to mortality in severe sepsis.
- 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.
- An innate anti-inflammatory cytokine profile (low level of tumor necrosis factor and high level of IL-10) is associated with fatal meningococcal disease.
- Polymorphisms in the genes that control the coagulation pathways are being evaluated. Patients with the prothrombotic factor V Leiden mutation are at higher risk of thrombotic complications, such as amputations and skin grafting but do not have increased mortality in meningococcemia.
- An increased type-1 plasminogen activator inhibitor response to tumor necrosis factor meningococcal septicemia was recently demonstrated to be due to a polymorphism in the PAI-1 gene.
- A recent study reported that a toll-like receptor 4 variant genotype was associated with increased mortality in children with invasive meningococcal disease.11
- Patients with anatomic or functional asplenia are also at increased risk for invasive meningococcal disease.
More on Meningococcal Infections |
 Overview: Meningococcal Infections |
| Differential Diagnoses & Workup: Meningococcal Infections |
| Treatment & Medication: Meningococcal Infections |
| Follow-up: Meningococcal Infections |
| Multimedia: Meningococcal Infections |
| References |
| Further Reading |
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Further Reading
The Clinician’s Guide to Recognition and Early Management of Meningococcal Disease in Children is a useful interactive resource. (Link used with permission from the Meningitis Research Foundation.)
Keywords
meningococcal infections, meningitis, infectious purpura fulminans, meningococcal meningitis, meningococcal septicemia, meningococcemia, invasive meningococcal disease, increased intracranial pressure, hypovolemia, pulmonary edema, intravascular thrombosis, purpura fulminans, varicella infection, hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, acidosis, hypoxia, hypoglycemia, obstructive hydrocephalus, sensorineural deafness, tachycardia, tachypnea, hypotension, maculopapular rash, neck stiffness, photophobia, bradycardia, treatment, diagnosis
