AUTHOR AND EDITOR INFORMATION

Section 1 of 13  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 13  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• Multimedia
• References

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).

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 gastrointestinal 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. 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.  

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. However, in the United Kingdom, more than 1400 laboratory-confirmed cases of meningococcal disease occur each year; most are caused by strains in serogroup B but a few cases of disease caused by strains in serogroups Y and W135 are reported. From 2004-2005, 88% of meningococcal cases in the United Kingdom were caused by strains in serogroup B.

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

Section 3 of 13  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• Multimedia
• References

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:⁷
• • 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)
  • 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.
• Patients with anatomic or functional asplenia are also at increased risk for invasive meningococcal disease.

DIFFERENTIALS

Section 4 of 13  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

• Haemophilus influenzae meningitis: The H influenzae type B vaccine caused the decline of meningitis related to this bacteria. Half of all childhood cases of bacterial meningitis are caused by N meningitidis, and most other cases are pneumococcal.
• Other causes of purpuric or petechial rash: Only 2-11% of children with petechial rash and fever have invasive meningococcal disease. Although most other children probably have viral infections, antibiotic therapy should be commenced without awaiting additional information. Distinguishing meningococcal disease from other causes in these cases is difficult, and the fatality rate is high. Other causes may include the following:
• • Bacterial infections - Pneumococcal septicemia, group A streptococcal septicemia, other gram-positive or gram-negative sepsis, syphilis
  • Viral infections - Epstein-Barr virus infection, enterovirus infection, measles, rubella, herpes simplex virus infection, cytomegalovirus infection, hemorrhagic viral fevers (eg, dengue)
  • Other infections - Mycoplasma infection (usually maculopapular), Rocky Mountain spotted fever, epidemic typhus, ehrlichiosis, leptospirosis, Candida infection
  • Platelet disorders - Immune thrombocytopenia, leukemia, other causes of bone marrow failure, Bernard-Soulier disease, Glanzmann disease
  • Clotting disorders - Hemophilia, von Willebrand disease, vitamin K deficiency, congenital or acquired protein C or S deficiency
  • Autoantibody-mediated causes - Often after varicella, group A hemolytic cause, Streptococcus or other viral (eg, rubella) infections, coumarin drugs, cholestasis, renal dialysis, nephrotic syndrome, bone marrow transplantation
  • Vasculitis - Henoch-Schönlein purpura, polyarteritis, antiphospholipid syndrome, other vasculitides, Kawasaki disease,
  • Trauma - Injury, violent coughing or emesis
  • Connective tissue disease - Osteogenesis imperfecta, Marfan syndrome, vitamin C deficiency
  • Miscellaneous - Cushing syndrome, hemolytic uremic syndrome, drug ingestion, erythema nodosum, erythema multiforme, spider and snake bites

WORKUP

Section 5 of 13  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• Multimedia
• References

Lab Studies

• The WBC count and C-reactive protein level may be elevated at presentation or may increase during the subsequent 24 hours.
• • These values are not reliable markers of infection.
  • In a study of 128 consecutive children with meningococcal sepsis who were admitted to a pediatric intensive care unit, only 14% had a WBC count of more than 20 X 10⁹/L, and 71% had a WBC count of less than 15 X 10⁹/L.
  • A low WBC count is a poor prognostic finding and should raise concerns about disease rapid progression.
• Coagulation is often disturbed in septicemia because of the consumption and loss of clotting factors.
• Biochemical disturbance is common in children who have shock with or without impaired renal function. The following abnormalities are common:
• • Hypokalemia despite acidosis
  • Hypocalcemia
  • Hypomagnesemia
  • Metabolic acidosis
• Rapid latex antigen tests may assist with diagnosis. The latex agglutination test has 50-100% sensitivity and high specificity, but it has a high rate of false-negative results.
• Rapid diagnosis with polymerase chain reaction using blood or CSF is being evaluated (91% sensitivity and specificity).
• Blood, throat, CSF, and skin aspirate cultures may help with diagnosis, but findings may be negative after outpatient administration of antibiotics. CSF cultures are positive in fewer than 50% of patients after the use of antibiotics.
• A convalescent serologic test may be useful.

Procedures

• In the presence of a purpuric or petechial rash, lumbar puncture may be hazardous and may add few data to aid in the diagnosis. In a patient with a depressed level of consciousness, shock, or any of the features listed below, lumbar puncture can be delayed, and treatment can immediately begin.
• The following are contraindications to lumber puncture (unless increased ICP is ruled out):
• • Prolonged or focal seizures
  • Focal neurological signs
  • Widespread purpuric or petechial rash
  • Glasgow Coma Scale score of less than 13
  • Pupillary dilatation or asymmetry
  • Impaired oculocephalic reflexes (ie, doll's eye reflexes)
  • Abnormal posture or movement, decerebrate or decorticate movement or cycling
  • Coagulation disorder
  • Papilledema
  • Hypertension
  • Signs of impending brain herniation (inappropriately low pulse, increased BP, irregular respiration)
• Although lumbar puncture is generally required to confirm the diagnosis of meningitis, some brainstem herniation (coning) seems to be temporally related to lumbar puncture. If safe to perform, lumbar puncture is useful to establish the presence of meningitis and to identify the causative organism and its antibiotic sensitivity to antibiotics.
• • CSF findings are characteristic in 90% of cases.
  • Findings may include the following:
  • • Neutrophil level - 100-60,000 cells/mL
    • Protein level - 100-1,000 mg/dL
    • CSF glucose - Less than 60% of plasma glucose
  • Results of CSF Gram staining are positive in 40-60% of acute bacterial meningitis cases, even after initial antibiotic treatment. However, results may be negative if antibiotics have been given on an outpatient basis.
  • Although lumbar puncture findings remain the criterion standard for diagnosis, the current practice is to avoid the procedure in any child with the contraindications listed above.

TREATMENT

Section 6 of 13  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• Multimedia
• References

Medical Care

Medical care should address community management, antimicrobial treatment, and emergency management of meningococcal septicemia and meningitis,¹ which may include treating shock and increased ICP and the use of new and experimental therapies.⁷

• Community management
• • Because mortality may be reduced with early antibiotic therapy, patients with a meningococcal rash should receive parenteral antibiotics by means of an intravenous or intramuscular route as soon as the diagnosis is suspected.
  • Intramuscular antibiotic injections may be less effective in a patient with shock and poor tissue perfusion.
  • For information regarding family practice recognition and management of meningococcal disease, see Media files 4-5.
• Antimicrobial treatment
• • A third-generation cephalosporin is the appropriate antibiotic until culture results are available. Although meningococcal infection is the most common bacterial cause of a petechial or purpuric rash and meningitis, other organisms (including H influenzae type B and Streptococcus pneumoniae) can cause shock and a nonblanching rash.
  • Empirical antibiotic therapy ensures coverage of likely meningeal pathogens when no rash is present, when the etiology of meningitis is uncertain, and when an immediate microbiological diagnosis is unavailable. This therapy can be modified in favor of appropriate specific therapy when the organism is grown or when its antibiotic sensitivities are known.
  • Although H influenzae type B is now an uncommon cause of meningitis in developed countries with modern vaccination programs, antibiotic therapy should cover this organism. Most cases of bacterial meningitis are due to N meningitides, and most other cases are due to S pneumoniae. In the United States, most cases are due to S pneumoniae.
  • Pneumococcal resistance to high-dose third-generation cephalosporins is reported in the United States and in some European countries, although resistance is unusual in the United Kingdom. For this reason and because untreated or partially treated bacterial meningitis has a poor outcome, the use of vancomycin and a third-generation cephalosporin is recommended for the treatment of suspected pneumococcal meningitis until the organism is identified and its sensitivities are known. Discontinue vancomycin after the microbial diagnosis and antibiotic sensitivities are established.
  • Empirical antibiotic therapy for meningitis based on age is as follows:
  • • Neonates - Ampicillin and cefotaxime (or ampicillin and gentamicin)
    • Infants aged 1-3 months - Ampicillin and cefotaxime with or without vancomycin
    • Older infants, children, and adults - cefotaxime or ceftriaxone with or without vancomycin
  • For information about emergency management of meningococcal disease in children, see Media files 2-3.
• Emergency management of meningococcal septicemia and meningitis
• • Although many meningococcal infections rapidly improve when treated with antibiotics, in some cases, meningococcal disease may progress rapidly; the time lag from the appearance of the first symptoms to death may be only a few hours.
  • Because the mortality rate is 10%, all patients with fever and petechial rash warrant urgent initial assessment and treatment and subsequent careful and repeated assessment. The initial assessment should be conducted to identify major clinical problems.
  • The following findings may help in the identification of severely ill patients whose condition may deteriorate and who are likely to need intensive care:
  • • Shock
    • Absence of meningitis
    • Rapidly extending rash
    • Low WBC count
    • Coagulopathy
    • Deteriorating level of consciousness
  • Shock and increased ICP, which are underlying processes in meningococcal disease that lead to death, may coexist. Increased ICP is more common in patients with only meningitis.
• Managing shock
• • After basic life support and antibiotics are administered, the next priority is treating shock. Basic life support should include the administration of oxygen at a rate of 10-15 L/min by means of a facial mask.
  • Any patient with cool extremities, prolonged capillary refill time, and tachycardia should be considered to have shock.
  • The initial therapy for shock is volume replacement at a rate of 20 mL/kg. In the United Kingdom, the use of 4.5% human albumin solution is generally recommended, although some US and UK centers use normal saline. A satisfactory response to volume replacement is a reduction in heart rate and improved peripheral perfusion. The first bolus of fluid may be repeated to achieve this response. The patient's condition may stabilize with only volume replacement, but the patient requires close monitoring and reassessment to detect further signs of shock or pulmonary edema (due to capillary leak syndrome).
  • Patients who do not respond to initial volume replacement require further volume replacement and may need inotropic support, such as the use of dopamine or dobutamine (10-20 mcg/kg/min), which may be administered via a peripheral vein until central venous access is established. Patients with persistent hypotension may need an infusion of adrenaline (0.1-5 mcg/kg/min), which must be administered via central venous access.
  • Endotracheal intubation and ventilation are recommended in patients who still have signs of shock after they have received volume replacement of more than 40 mL/kg. Even patients who are apparently awake and alert have a high risk of pulmonary edema.
  • Some patients require fluid replacement with as much as twice their circulating blood volume in the first hours after presentation, but additional volume should be administered only after positive pressure ventilation is established.
  • Biochemical correction of acidosis, hypoglycemia, hypokalemia, hypocalcemia, and hypomagnesemia is usually required.
  • Correct coagulopathy and anemia with the use of fresh frozen plasma and blood, as appropriate.
• Managing raised ICP
• • Suspect increased ICP if the patient has a decreased level of consciousness; focal neurological signs; unequal, dilated or poorly reacting pupils; abnormal posturing or seizures; relative hypertension or bradycardia; or if the patient is agitated or combative. Papilledema is a late sign; therefore, its absence should not reassure the treating team because raised ICP can still be present.
  • After initiating basic life support principles and administering antibiotics, the therapeutic goal is to maintain oxygen and nutrient delivery to the brain. For this reason, shock must be corrected in individuals with both shock and increased ICP to maintain cerebral perfusion pressure. After correcting shock with volume replacement and inotropic support as necessary, cautiously manage the fluid balance to avoid further increasing the ICP.
  • Consider the use of mannitol (0.25 g/kg IV over 10 min), followed by furosemide (1 mg/kg intravenously) when increased ICP is suspected. These drugs can help control the ICP during elective intubation.
  • Immediately institute measures to stabilize the ICP; these measures may include intubation and ventilation in order to control PaCO2 between 4-4.5 kPa, sedation and muscle relaxation, and elevating the patient's head by 30 degrees.
  • Find and correct biochemical abnormalities.
  • Do not attempt lumbar puncture.
  • Treat seizures, if present, using standard resuscitation guidelines
• Treatment of patients with limited shock and no increased ICP
• • Reassess these patients and patients who respond rapidly to minimal volume replacement for signs of deterioration during the first 48 hours following admission.
  • The use of corticosteroids in meningitis may be considered. Several studies revealed that adjunctive dexamethasone reduces sensorineural hearing loss (but not mortality or other neurological sequelae) in children and infants with H influenzae type B meningitis. Few adverse effects occur with dexamethasone administration. No reports of delayed CSF sterilization or treatment failure are known. A meta-analysis of findings from randomized controlled trials suggests that such treatment has a benefit in preventing sequelae in both this and pneumococcal meningitis in childhood.
  • Although data are poor for meningococcal meningitis, the pathophysiologic events are likely to be similar to those of other forms of bacterial meningitis. In some animal models, anti-inflammatory therapy was beneficial. No evidence of the benefits of steroid use in patients with septic shock is known, and steroid use is necessary only with meningitis. If hypoadrenalism is suspected because of resistance to large doses of inotropic drugs, administer adrenal replacement doses of hydrocortisone. Steroids have not been proven helpful in septicemia.
• New and experimental therapies for meningococcal septicemia: Although new and experimental therapies have been proposed, none have proven to reduce mortality or morbidity. Therapies include the following:
• • Antiendotoxin agents: An international multicenter randomized controlled trial of the antiendotoxin recombinant bactericidal permeability-increasing protein was recently completed at centers in the United Kingdom and United States.⁸ Despite a strong trend in reducing mortality and amputations, the benefits were not statistically significant. Further studies are being designed. A randomized trial of the use of antiendotoxin monoclonal antibody HA1A in children with meningococcemia showed a 32% reduction in mortality, but the result was not statistically significant (n = 269, P = .110).
  • Anticytokine response agents (eg, monoclonal antibody against tumor necrosis factor⁹)
  • Leukocyte activation antagonists (eg, corticosteroids)
  • Peripheral vasodilators (eg, prostacyclin)
  • Agents for the treating disseminated intravascular coagulation (eg, protein C¹⁰ or activated protein C¹¹)
  • Agents for treating acute respiratory distress syndrome (eg, extracorporeal membrane oxygenation [randomized controlled trials not performed])
  • Miscellaneous agents (eg, hemodiafiltration [randomized controlled trials not performed])

Surgical Care

• Anecdotally, fasciotomy may preserve limb and digit function in severe meningococcal septicemia when impending peripheral gangrene and increased compartment pressures are present.
• Consult an orthopedist, vascular surgeon, or both.
• Measure compartment pressures and assess peripheral pulses with Doppler ultrasonography when patients have impaired limb perfusion or severe edema.
• Avoid early limb amputation because significant tissue recovery may occur as the disease progresses.

MEDICATION

Section 7 of 13  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• Multimedia
• References

Drug Category: Antibiotics

Mortality may be reduced with early antibiotic therapy; however, antibiotics may be less effective in patients with shock or poor tissue perfusion. Regarding community management, because mortality may be reduced with early antibiotic therapy, patients with a meningococcal rash should receive parenteral benzyl penicillin by means of an intravenous or intramuscular route as soon as the diagnosis is suspected. Intramuscular antibiotic injections may be less effective in a patient with shock and poor tissue perfusion. Give cefotaxime, ceftriaxone, or chloramphenicol to patients who are allergic to penicillin.

Empirical antibiotic therapy ensures coverage of likely meningeal pathogens when no rash is present, when the etiology of meningitis is uncertain, and when immediate microbiological diagnosis is unavailable. This approach can be modified in favor of appropriate specific therapy when the organism is identified or when its sensitivities to antibiotics are known. Empirical antibiotic therapy for meningitis based on age is as follows:

• Neonates - Ampicillin and cefotaxime
• Infants aged 1-3 months - Ampicillin and cefotaxime with or without vancomycin
• In older infants, children, and adults - Cefotaxime or ceftriaxone with or without vancomycin

Drug Name	Chloramphenicol (Chloromycetin)
Description	Can be used in patients with penicillin and cephalosporin allergy.
Adult Dose	Community first dose: 1.2 g IV
Pediatric Dose	Community first dose: <12 years: 25 mg/kg IV >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Toxicity may increase with concurrent barbiturates, (serum levels may decrease, barbiturate levels may increase); manifestations of hypoglycemia may occur with sulfonylureas; rifampin may reduce serum levels, presumably by means of hepatic enzyme induction; may increase effects of anticoagulants; may increase serum hydantoin levels, possibly resulting in toxicity
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Use only for indicated infections or as prophylaxis for bacterial infections; serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) can occur; perform blood studies at baseline and approximately q2d during therapy; discontinue with reticulocytopenia, leukopenia, thrombocytopenia, anemia, or findings attributable to chloramphenicol; adjust dose in liver or kidney dysfunction; caution in pregnancy at term or during labor because of potential toxic fetal effects (gray syndrome)

Drug Name	Ampicillin (Marcillin, Omnipen, Polycillin, Principen, Totacillin)
Description	Used for empiric treatment in neonates aged 0-3 mo to cover possible listeriosis.
Adult Dose	1-2 g IV q4-6h
Pediatric Dose	200-400 mg/kg/d IM/IV divided q4-6h
Contraindications	Documented hypersensitivity
Interactions	Probenecid and disulfiram elevate levels; allopurinol decreases effects and has additive effects in ampicillin rash
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction

Drug Name	Cefotaxime (Claforan)
Description	First-line antibiotic for empiric therapy of meningitis or sepsis while culture and susceptibility data are pending. Cefotaxime or ceftriaxone are the preferred agents for the treatment of confirmed meningococcal disease.
Adult Dose	1-2 g IV/IM q4h
Pediatric Dose	Infants and children: 300 mg/kg/d IV/IM divided q6h >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase levels; coadministration with furosemide and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose in severe renal impairment; associated with severe colitis

Drug Name	Ceftriaxone (Rocephin)
Description	First-line antibiotic for empiric therapy of meningitis or sepsis while culture and susceptibility data are pending; cefotaxime or ceftriaxone are the preferred agents for the treatment of confirmed meningococcal disease.
Adult Dose	Treatment: 1-2 g IV qd or divided bid; not to exceed 4 g/d Chemoprophylaxis: 250 mg IM as single dose
Pediatric Dose	Treatment: 80 mg/kg IV bid for 2 d then qd for 5 d Chemoprophylaxis: <12 years: 125 mg IM as single dose >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Adjust dose in renal impairment; caution in breastfeeding women and allergy to penicillin

Drug Name	Vancomycin (Lyphocin, Vancocin, Vancoled)
Description	Used for empiric management of sepsis and meningitis with risk of resistant pneumococcal infection. Has no activity against gram-negative bacteria, including meningococci.
Adult Dose	0.5-2 g/d IV divided tid/qid for 7-10 d
Pediatric Dose	60 mg/kg/d IV divided q8h
Contraindications	Documented hypersensitivity
Interactions	Erythema, histamine-like flushing, and anaphylactic reactions may occur when administered with anesthetic agents; nephrotoxicity may increase with concurrent aminoglycoside monotherapy; may enhance neuromuscular blockade effects with coadministration of nondepolarizing muscle relaxants
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in renal failure, neutropenia; too-rapid IV infusion (dose administered in a few minutes) may cause "red man" syndrome (rare with 2-hour administration), which is not an allergic reaction

Drug Name	Ciprofloxacin (Cipro)
Description	Used for chemoprophylaxis of N meningitides infection in adults.
Adult Dose	500 mg PO once for prophylaxis only
Pediatric Dose	<18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Adjust dose in renal function impairment

Drug Name	Rifampin (Rifadin, Rimactane)
Description	Used for chemoprophylaxis of N meningitides infection.
Adult Dose	Chemoprophylaxis: 600 mg PO bid for 2 d
Pediatric Dose	Chemoprophylaxis: <1 year: 5 mg/kg PO bid for 2 d 1-12 years: 10 mg/kg PO bid for 2 d; not to exceed 600 mg/dose >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Induces CYP450 microsomal enzymes (ie, may decrease effects of acetaminophen, PO anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin); blood pressure may increase with coadministration of enalapril
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Not applicable to short-term prophylaxis therapy

Drug Category: Vasopressors

After basic life support and administration of antibiotics, treating shock is the next priority.

Drug Name	Dobutamine (Dobutrex)
Description	First-line drug in meningococcal sepsis without central venous access; produces vasodilation and increases inotropic state; higher doses may increase heart rate and exacerbate myocardial ischemia; may be given via peripheral cannula prior to central venous access.
Adult Dose	5-20 mcg/kg/min IV; titrate by 5 mcg/kg/min for response; if no response with 20 mcg/kg/min, add dopamine 5-20 mcg/kg/min until epinephrine can be administered via central venous access
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; idiopathic hypertrophic subaortic stenosis; atrial fibrillation or flutter
Interactions	Beta-adrenergic blockers antagonize effects of dobutamine; general anesthetics may increase toxicity
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Following a myocardial infarction use with extreme caution; hypovolemic state should be corrected before using this drug

Drug Name	Epinephrine (Adrenaline)
Description	For persistent hypotension. Has alpha-agonist effects (eg, increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability) and beta-agonist effects (eg, bronchodilatation, chronotropic cardiac activity, positive inotropic effects).
Adult Dose	0.1-5 mcg/kg/min IV
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; cardiac arrhythmias or angle-closure glaucoma; local anesthesia in areas such as fingers or toes (vasoconstriction may cause tissue sloughing)
Interactions	Increases toxicity of beta-blocking and alpha-blocking agents and of halogenated inhalational anesthetics
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in prostatic hypertrophy, hypertension, cardiovascular disease, diabetes mellitus, hyperthyroidism, cerebrovascular insufficiency; rapid IV infusions may cause death from cerebrovascular hemorrhage or cardiac arrhythmias; use extravasation precautions

Drug Category: Osmotic diuretics

These agents are used to control ICP during elective intubation. These agents raise the osmolality of plasma and renal tubular fluid, which creates an osmotic inhibition of water transport in the proximal tubule. This subsequently decreases the gradient for passive sodium absorption in the ascending limb of the loop of Henle. The increased urinary flow is achieved by a nonelectrolyte solute diuresis. Increases glomerular filtration rate may also be observed.

Drug Category: Diuretics

These agents promote excretion of water and electrolytes by the kidneys.

Drug Category: Glucocorticoids

These agents elicit anti-inflammatory and immunosuppressive properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

FOLLOW-UP

Section 8 of 13  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• If shock or increased ICP is present, experienced staff should transfer the child to a pediatric intensive care unit as soon as possible.
• Initially manage simple meningitis or sepsis that requires minimal intervention with regular cardiovascular (eg, pulse, blood pressure, capillary refill time) and neurological observation. Later, transfer the pediatric patient to a general medical pediatric ward if possible.

Further Outpatient Care

Follow-up care at least 6 weeks after meningococcal infection should include the following:

• Ongoing management of specific complications such as amputations, skin grafting, or renal failure
• Full physical examination
• Assessment of plasma complement levels (eg, total hemolytic complement, C3, and C4, with or without properdin)
• Serological confirmation of the diagnosis if no diagnosis was made at the time of presentation
• Audiologic function testing
• Basic assessment psychological status after intensive care, if relevant
• Possible vaccination of contacts if an outbreak of group A, C, Y, or W135 disease occurs

Transfer

• Transfer to a pediatric intensive care unit is necessary in approximately 20% of pediatric cases.
• After extubation, transfer pediatric patients to a general pediatric ward.

Deterrence/Prevention

• Prevention of secondary cases
• • Household contacts of patients with meningococcal disease are 100-800 times more likely to contract the disease than the general population in the year after the index case. Risk of secondary cases in contacts decreases with time.
  • Chemoprophylaxis with rifampicin, ciprofloxacin, or ceftriaxone is currently offered to household and intimate contacts of the index case if meningococcal disease is suspected or proven. Ceftriaxone is preferred in children who refuse oral medication and may be used in pregnancy.
  • Current UK guidelines advise chemoprophylaxis be given only to household contacts (including those living or sleeping in the same house, pupils in the same dormitory, boyfriends/girlfriends, and university students sharing the same kitchen in halls of residence). Anyone who has had a transient close contact with the patient and has been directly exposed to respiratory secretions around the time of admission to the hospital should also receive prophylaxis. Other contacts do not require prophylaxis because the benefits of giving antibiotics in this setting are unknown; clusters in these settings are rare, and harm may arise from drug side effects, development of antibiotic resistance, and eradication of nonpathogenic organisms that may generate cross-protective immunity.
  • US guidelines recommend chemoprophylaxis be given to individuals in childcare facilities or nurseries who had contact with the patient in the 7 days before the illness onset and also be given to any contacts who have had direct exposure to secretions from the patient, such as kissing or sharing toothbrushes or eating utensils, during the 7 days before the illness onset. In addition, those who have frequently eaten or slept in the same dwelling as the patient in the preceding 7 days should be given prophylaxis.
  • Chemoprophylaxis is recommended for health care workers who are exposed to aerosol secretions from the patient (eg, those performing tracheal intubation) because they are 25 times more likely to contract the disease than the general population.
  • Because the rate of disease in secondary contacts is highest immediately after the onset of the disease in the patient, chemoprophylaxis should be administered as soon as possible, preferably within 24 hours. If chemoprophylaxis is delayed by more than 14 days, it is probably of limited value but is still recommended until 4 weeks after the patient's presentation.
  • Close contacts of patients with proven group C meningococcal infection should receive the protein-polysaccharide conjugate group C vaccine or the A/C polysaccharide vaccine.
  • Antibiotic chemoprophylaxis of N meningitides may involve the use of rifampicin, ceftriaxone, and/or ciprofloxacin (adults only).
• Vaccination^{12, 13}
• • Meningococci are gram-negative diplococci. Pathogenic strains are enveloped in a polysaccharide capsule, which facilitates invasion and which is an obvious target for candidate vaccines. The serogroup of the organism is assigned from the reaction of sera to the polysaccharide capsule.
  • Purified polysaccharide vaccines against encapsulated bacteria, such as meningococci, Haemophilus, and pneumococci, are poorly immunogenic in young children. Protein-polysaccharide conjugate vaccines for H influenzae type B are protective in infants and have greatly reduced the prevalence of disease caused by this organism.
  • The conjugate vaccine for group C meningococci contains serogroup C meningococcal polysaccharide is conjugated to the protein CRM197. It appears to be immunogenic in young children and was administered to all children during 1999-2000 in the United Kingdom. In January 2001, the short-term effectiveness of this vaccine in England was reported to be 97% (95% confidence interval [CI]: 77%, 99%) for teenagers and 92% (95% CI: 65%, 98%) for toddlers. These early results confirm the superiority of this vaccine compared with plain C polysaccharide vaccines, which are ineffective in young children.
  • The UK immunization schedule has recently changed to include a meningococcal booster at 12 months (combined with Hib booster) because studies showed that the efficacy of the vaccine declined at 1 year to around 80%.
  • In the United States, 2 meningococcal vaccines are available. MPSV4 (meningococcal polysaccharide vaccine) is recommended for use only in individuals aged 2-10 years who are at increased risk of meningococcal disease, such as those with terminal complement deficiencies and asplenia. The conjugate vaccine MCV4 is given to all children aged 11-12 years or at entry to high school or college if previously unvaccinated.
  • Purified polysaccharide is not a good immunogen in young children, and the previously approved meningococcal vaccines (A, C, Y, and W135 or A and C) are used only to protect travelers, for prophylaxis of household contacts of patients with proven serogroup C disease, or to control outbreaks of serogroup C disease in discrete communities.
  • Vaccines against group B serotypes are difficult to make. Because the polysaccharide capsule of the group B meningococcus is chemically and antigenically identical to human brain and fetal antigens, it is poorly immunogenic in humans, and its use might induce autoimmunity.
  • Other bacterial components, such as bacterial outer membrane proteins, are being investigated for use in vaccines. Vaccines have been prepared by using simple complexes of these proteins. Recent vaccines involve outer membrane vesicles and contain outer membrane proteins in spheres of the bacterial lipid membrane.
  • Although some serogroup B vaccine trials demonstrate an overall efficacy of more than 50%, protection for the most vulnerable age group has not been demonstrated. In those individuals with a detectable immune response, serum bactericidal activity after vaccination seems to be limited to the strain in the vaccine.

Complications

Complications of meningococcal infection may include the following:

• Cardiorespiratory failure that requires tracheal intubation and inotropic support
• Renal failure that requires hemofiltration, hemodialysis, or peritoneal dialysis
• Neurological failure
• Severe peripheral gangrene that leads to skin grafting and (late) amputation
• Peritoneal compartment syndrome due to severe abdominal capillary leak that requires placement of a tap
• Immune complex disease leading to arthritis, pericarditis, myocarditis, and pneumonitis 10-14 days after the primary infection
• Psychological disturbance after intensive care or complications

Prognosis

• Isolated meningococcal meningitis (5% mortality rate) has a better prognosis than meningococcal septicemia (10-40% mortality rate).
• Specialty units in geographical areas with a high incidence now have mortality rates of less than 5%.
• In the United Kingdom, approximately 5% of survivors will have neurological sequelae, mainly sensorineural deafness. Amputation or skin grafting due to digital or limb ischaemia and severe skin necrosis may be required in 2-5% of survivors.
• In the United States in 2005, a study reported 11-19% of survivors had serious health sequelae, including sensorineural hearing loss, amputations, and cognitive impairment.

Patient Education

• Health education improves public recognition of a nonblanching rash 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 excellent patient education resources, visit eMedicine's Children's Health Center and Brain and Nervous System Center. Also, see eMedicine's patient education articles Meningitis in Children and Brain Infection.

MISCELLANEOUS

Section 9 of 13  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to recognize or consider shock in children may lead to inadequate resuscitation and treatment.
• Inappropriate lumbar puncture is common. This investigation must not be performed in patients in whom ICP may be increased. A normal CT scan is not evidence of normal ICP in bacterial meningitis.
• Symptoms are often nonspecific.
• Any child with a nonblanching petechial or purpuric rash should be considered to have meningococcal disease until proven otherwise.
• The condition of children with this illness can deteriorate quickly, and any patient in whom meningococcal disease is suspected or considered must have regular observations and clinical review to ensure any signs of deterioration are picked up early and appropriate therapy is instituted.

Special Concerns

• Although increasingly well recognized and managed in children, meningococcal disease often is poorly managed in adults in medical settings.
• Fluid resuscitation may not be sufficiently aggressive, early intubation often is not considered, and the rapidity of disease progression in an adult often is not understood.

FURTHER READING

Section 10 of 13  

• Authors and Editors
• Introduction
• Clinical