AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
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• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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Background

Neisseria meningitidis is an encapsulated gram-negative diplococcus and the causative agent of meningococcemia. Acquisition of the organism can result in asymptomatic pharyngeal colonization or invasive disease. Dissemination of meningococci into the bloodstream defines meningococcemia and is a medical emergency, making early recognition of the disease essential.

Patients with acute meningococcal infection can present clinically with one of 3 syndromes: meningitis, meningitis with meningococcemia, or meningococcemia without obvious meningitis. Prior to the advent of antibiotics, almost all cases ended in death or marked morbidity.

Pathophysiology

Humans are the only natural reservoir and can transmit meningococci by aerosols or secretions from their nasopharynx. Infection is preceded by colonization of the nasopharynx. Attachment to the nasopharyngeal epithelial cells is aided by pili that the meningococci express. These bind to human cell surface protein CD 46. 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 carriers are asymptomatic. In outbreaks, the carriage rate can be as high as 35%. For intimate contacts of patients with meningococcemia, a 100- to 1000-fold increased risk of acquiring infections exists.

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.¹

Meningococci have 3 important virulence factors, as follows:

• A polysaccharide capsule that enables the organism to resist phagocytosis
• A lipo-oligosaccharide endotoxin that can be shed in large amounts by a process called blebbing, causing fever, shock, and other pathophysiology
• An immunoglobulin A1 protease that cleaves lysosomal membrane glycoprotein-1 (LAMP1), helping the organism survive intracellularly

Immune individuals have bactericidal antibodies against cell wall antigens and capsular polysaccharide. Deficiency of circulating antimeningococcal antibodies is associated with disease.

Impairment of the protein C anticoagulation pathway leads to the development of purpura fulminans in meningococcemia.

Endotoxin, cytokines, and free radicals damage the vascular endothelium, producing platelet deposition and vasculitis.

Frequency

United States

The incidence of meningococcal disease in the United States is estimated to be 0.7-1.4 cases per 100,000 population. The case-fatality rate is approximately 10%. The incidence and case fatality rates have been relatively constant. While serogroups B and C are most common, increase in serogroup Y disease has been noted in the 1990s.

An outbreak is characterized by the occurrence of 3 or more cases in a 3-month period or a primary attack rate of at least 10 cases per 100,000 population.

International

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

In the United Kingdom, the number of cases and deaths from meningococcal disease rose in 1995, mainly due to serogroup C disease. This declined when serogroup C conjugate vaccine was introduced in the national immunization program.²

The African meningitis belt is a region where serogroup A meningococcal disease has been endemic for over a century. It extends from Ethiopia in eastern Africa to Senegal in West Africa.

Outbreaks have occurred during the annual hajj (pilgrimage) in Saudi Arabia in 2000 and 2001 among pilgrims and household contacts.^{3, 4} Outbreaks have also occurred in Africa, parts of Asia, South America, and the former Soviet republics. Serogroup A is usually implicated in these epidemics. Outbreaks are occasionally reported in the United States as well.

Up to 95% of patients with meningococcal disease have meningococcemia and/or meningitis. Up to 50% have meningococcemia without meningitis. Fulminant meningococcemia occurs in up to 20% of individuals. Nosocomial transmission to patient care personnel and laboratory staff is rare.

Mortality/Morbidity

The case-fatality rate is approximately 10% for meningococcal meningitis and 20% for meningococcemia despite therapy with antimicrobial agents.

• The mortality rate of fulminant infection remains high, with most deaths occurring within 48 hours.
• In industrialized countries, the mortality rate can exceed 50%; in developing countries, it is higher and can approach 70%.

Race

In the United States, the incidence of meningococcal disease is higher in blacks and in lower socioeconomic groups.

Sex

Incidence in males is somewhat higher (1.2 cases per 100,000) than in females (1.0 case per 100,000).

Age

• In epidemic cases, people of any age may be affected, with the case distribution shifted to older individuals.
• The attack rate for endemic meningococcal disease is highest for children aged 6-36 months. Children younger than 6 months are protected by maternal antibodies. In New York City, during the period from 1989-2000, the overall incidence rates of meningococcal disease decreased. This was more evident in the younger age groups, and this increased the median age of patients from 15 years in 1989-1991 to 30 years in 1998-2000.⁵
• Occult meningococcemia is an uncommon form of infection that affects children aged 3-24 months.

CLINICAL

Section 3 of 11  

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History

A nonspecific prodrome of cough, headache, and sore throat may be present. This is followed by rapid onset of fever with chills, arthralgias, and myalgias. The potential rapidity of progression cannot be stressed enough.

• In fulminant meningococcemia, collapse occurs within a few hours, with rapid enlargement of petechiae and purpuric lesions.
• If meningitis is present with meningococcemia, then headache, neck stiffness, lethargy, and drowsiness may be present.
• Decreased mentation and coma may be present.
• Young children may present with sudden onset of fever and lethargy. They may also have vomiting and convulsions.
• In chronic meningococcemia (a rarity), painful skin lesions are present on the extremities, similar to those seen in gonococcemia, with migratory polyarthritis and tenosynovitis. Antibiotic treatment effects a prompt response.

Physical

Patients appear severely ill.

• Tachycardia and mild hypotension are present.
• Fever is moderate. High fever is present in fulminant meningococcemia.
• A petechial rash is present in 50-80% of patients. It involves the axillae, flanks, wrists, and ankles. Petechiae are often located in the center of lighter-colored macules. Lesions commonly begin on the trunk and legs in areas where pressure is applied. Confluence of lesions results in hemorrhagic patches, often with central necrosis.
• Congestive heart failure, gallops, and pulmonary edema may be present. Other evidence of end-organ damage may also rapidly appear.
• In fulminant meningococcemia, rapid clinical worsening is observed, with hypotension and respiratory failure.
• Pericarditis can occur during the acute disease or in the recovery period. Pericarditis is associated with serogroup C disease.

Causes

Meningococci (0.6 X 0.8 µm) are gram-negative single cocci or diplococci with flattened adjacent sides. Older cultures can vary considerably in size and shape. A polysaccharide capsule is present, and this is the basis of serotyping. They grow on media that contains blood at temperatures of 35-37°C in a moist atmosphere reduced in oxygen and containing 5-19% carbon dioxide.

• Seroagglutination can segregate meningococci into 13 serogroups: A, B, C, D, X, Y, Z, E, W-135, H, I, K, and L. Ninety-eight percent of infections are caused by encapsulated serogroups A, B, C, Y, and W-135.
• Individuals with complement component deficiencies have an increased susceptibility to meningococcal infections.
• Recurrent meningococcemia has also been reported with immunoglobulin G2 subclass deficiency.

DIFFERENTIALS

Section 4 of 11  

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WORKUP

Section 5 of 11  

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Lab Studies

• Definitive diagnosis requires culture of meningococci from blood, spinal fluid, joint fluid, or, occasionally, from skin lesions.
• • Findings on blood cultures are positive in 60-80% of untreated patients.
  • Findings on cerebrospinal fluid (CSF) cultures are positive in up to 70% of untreated patients.
• Polymorphonuclear leukocyte levels are usually elevated, but they may be within the reference range or low.
• Thrombocytopenia may be present.
• In meningitis, CSF pressures are elevated, with elevated protein levels and low glucose levels.
• • Findings on CSF Gram stain are positive in about 50% of patients with meningococcal meningitis.
  • Detection of meningococcal capsular polysaccharide in CSF may be used for rapid diagnosis. It is sensitive for A and C polysaccharides.
• Gram-negative diplococci may be observed in punch biopsy and needle aspiration specimens of skin lesions or buffy coat preparations. Gram-negative diplococci may also be recovered from joint fluid. Findings on Gram stains of skin lesions remain positive for up to 2 days after the start of antibiotics and form a rapid means of diagnosis, including in cases in which meningitis is not present or in which findings on spinal fluid culture are negative owing to the administration of antibiotics.
• Polymerase chain reaction (PCR) is a rapid method for diagnosing CSF infection. It may not be available commercially in the United States but has been used extensively in the United Kingdom. The sensitivity and specificity of PCR of spinal fluid in the diagnosis of meningococcal meningitis is greater than 90%. It is useful in cases in which antibiotics have been administered. It can also be used to rapidly type strains in developing epidemics.

Imaging Studies

• Chest radiograph is useful to evaluate for pneumonia and acute respiratory distress syndrome.
• Echocardiography can be used to evaluate myocardial dysfunction and the development of pericarditis.

Procedures

• Lumbar puncture is used to test for meningitis.
• • Stain and culture of fluid
  • WBC count and differential
  • Total protein level
  • Glucose level

Staging

Evaluate for evidence of other end-organ damage (eg, kidney or hepatic failure) with appropriate blood tests.

TREATMENT

Section 6 of 11  

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Medical Care

Hospitalization is required for severely ill patients with fever, headache, and petechial rash.

• Begin antibiotic treatment promptly.
• Suspect fulminant meningococcemia if hypotension and severe coagulation abnormality are present. In such cases, monitoring in an intensive care setting is required.
• Other than antimicrobial treatment, supportive measures to correct circulatory collapse may be needed.
• Any adrenal insufficiency requires corticosteroid replacement.

Surgical Care

• Arterial occlusion caused by intravascular clotting in the extremities may require amputation.
• Pericardiocentesis may be required if pericarditis is complicated by tamponade.

Consultations

• Consult an infectious diseases specialist.
• Surgical consultation is needed in gangrene of the extremities.
• Consultation with a hematologist may be needed to manage the coagulopathy.
• Consultation with a cardiologist may be needed if evidence of heart failure or the occurrence of pericarditis exists.

Activity

Activity is determined by the severity of the illness presentation. In most severe cases, patients are bed bound.

MEDICATION

Section 7 of 11  

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Antimicrobial therapy is directed toward treatment of active infection or used prophylactically to protect those exposed to the infective organism through close contact.

Drugs effective in treating active meningococcal infection include penicillin G, chloramphenicol in patients who are allergic to penicillin, and some cephalosporins (ie, cefotaxime, ceftriaxone, cefuroxime) used to treat pediatric patients. Meningococcal resistance to penicillins has occurred; the mechanism of resistance involves altered penicillin-binding proteins. Sulfonamides have a limited role in meningococcal infections because of the resistance of serogroups A, B, and C; these are not discussed further in this article. Duration of treatment is dictated by clinical response and manifestation of disease, although 10-14 days should be sufficient with a sensitive organism.

Individuals with at least 4 hours of close contact during the week before onset of illness have an increased risk of being infected. Individuals at risk include housemates, daycare contacts, cellmates, or individuals exposed to infected nasopharyngeal secretions (eg, through kissing, mouth-to-mouth resuscitation, intubation, suctioning).

Rifampin and ciprofloxacin are commonly used for chemoprophylaxis. Other agents include ceftriaxone and azithromycin. A single dose of intramuscular ceftriaxone may be used in children or adults. Spiramycin is the primary prophylactic regimen used in many European countries. Vaccination with monovalent A; monovalent C; bivalent A-C; or quadrivalent A, C, Y, and W-135 vaccine should be an adjunct to antibiotic chemoprophylaxis of susceptible contacts in epidemics. The Centers for Disease Control and Prevention (CDC) has issued new (2007) guidelines for the use of meningicoccal vaccinations. In addition, the Advisory Committee on Immunization Practices (ACIP) recently issued updated adult vaccination scheduling guidelines for October 2007 through September 2008.

The eradication of carriage is also indicated in the index case unless third-generation cephalosporins have been used.

A single intramuscular dose of an oily suspension of chloramphenicol has been shown to be as effective as 5 days of penicillin in persons with meningococcal meningitis, and this may be useful in resource-poor countries.

Drug Category: Antimicrobial agents

Used to treat active meningococcal infection.

Drug Category: Antimicrobial agents, chemoprophylaxis

Protect individuals who are at risk because of close contact with patients who have meningitis.

Drug Category: Inactivated bacteria

Used to induce active immunization.

FOLLOW-UP

Section 8 of 11  

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Further Inpatient Care

• Patients should complete a course of antimicrobial therapy.
• Manage any complications appropriately.
• Discontinue respiratory isolation precautions after 24 hours of antibiotics.
• Supportive care may be needed, including maintenance of fluid and electrolyte balance and vasoactive drugs in shock (eg, dopamine).
• Monitor blood pressure, urine output, and cardiac function.
• Closely monitor platelets, fibrin, and fibrin degradation products.
• Some studies have shown inconclusive benefits with the use of low-dose steroids.
• No proof shows that unconventional treatments have a significant impact on outcome in meningococcemia.
• Currently, early recognition and appropriate treatment seem to be the optimal methods of improving outcome. However, a bactericidal/permeability-increasing (BPI) protein, a natural protein stored within the neutrophil granules that binds to and neutralizes the effects of endotoxin in vitro, in laboratory animals, and in humans, has shown some promise in clinical trials in children with severe meningococcal sepsis.
• Make sure all significant contacts of the patient have been evaluated for prophylaxis as appropriate.

Further Outpatient Care

• Observe for any late neurologic sequelae.
• Pericarditis can occur while patients are recuperating from meningococcemia. Consider pericarditis if fever with shortness of breath on minimal exertion occurs during the recovery period.
• Late skeletal deformities are rare, but epiphyseal avascular necrosis and epiphyseal-metaphyseal defects have been described. These usually occur in the lower extremities and result in angular deformity and inequality of leg length.

Transfer

• Once the patient is stabilized, attempt transfer to a tertiary care center because meningococcal sepsis frequently produces multisystem organ dysfunction.

Deterrence/Prevention

• Meningococcal polysaccharide vaccine is used for immunization of individuals older than 2 years. The CDC has issued new (2007) guidelines for the use of meningicoccal vaccinations. The tetravalent vaccine contains A, C, Y, and W135 polysaccharides. It is safe and effective. It is useful in aborting outbreaks caused by serogroups represented in the vaccine and therefore should be used in their control. Administer in the following groups:
• • Immunization of military recruits
  • Routine immunization of travelers to areas where epidemics occur (eg, as per Saudi requirements, individuals traveling for the hajj pilgrimage)
  • Immunization of individuals with complement deficiencies or asplenia
• To lessen the risk of infection in the clinical setting, staff caring for patients with known or suspected meningococcal infections should wear masks in addition to standard precautions.
• Antibiotic prophylaxis may be needed if intensive direct contact with patients has occurred in the absence of appropriate precautions.
• • Prophylaxis aims to produce long-term (ie, 3-4 wk) eradication of meningococci from the nasopharynx using short-term antibiotics.
  • Treatment must be initiated immediately if prophylaxis is deemed necessary. The tetravalent vaccine must be administered to all intimate contacts of the index case.

Complications

• Disseminated intravascular coagulation
• Vasomotor collapse and shock
• Meningitis
• Seizures or deafness in the acute stages of meningitis
• Postmeningitic epilepsy (rare)
• Coma
• Thrombocytopenia
• Septic arthritis
• Herpes labialis (5-20% of patients with meningococcal disease)
• Immune complex arthritis involving multiple joints
• Pericarditis
• Bacterial endocarditis
• Myocarditis
• Gangrene
• Urethritis and endometritis
• Osteomyelitis
• Purulent conjunctivitis and sinusitis

Prognosis

• Patients with terminal complement component deficiency have a more favorable prognosis.
• A fatal outcome is associated with properdin deficiencies.
• Coagulopathy with partial thromboplastin time greater than 50 seconds or fibrinogen concentration less than 150 µg/dL indicates a poor prognosis.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• In nonoutbreak situations, health care workers who are asymptomatic carriers do not need to be identified, treated, or removed from patient care.
• Make sure that the local department of health is notified of suspected and/or proven cases to assist in evaluation of close contacts and prophylaxis.
• Watch for pericarditis and tamponade in the recovery period.

Special Concerns

• Chemoprophylaxis should be administered to intimate household, daycare center, and nursery school contacts of sporadic cases. Vaccinate household and other intimate contacts.
• The safety of the meningococcal polysaccharide vaccine in pregnant women has not been evaluated, and it should be avoided unless the risk of infection is high. The vaccine is also not routinely indicated for health care workers in the United States. The vaccine, similar to other polysaccharide vaccines, is not immunogenic in children younger than 2 years because of unknown reasons.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Dorsum of the hand showing a petechial rash. Courtesy of Professor Chien Liu.
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Media file 2:  Petechial lesions on the palm. Courtesy of Professor Chien Liu.
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Media file 3:  Petechial rash on lower extremities. Courtesy of Professor Chien Liu.
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Media file 4:  Conjunctival petechiae. Courtesy of Professor Chien Liu.
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Media file 5:  Gram-negative intracellular diplococci. Courtesy Professor Chien Liu.
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REFERENCES

Section 11 of 11

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Article Last Updated: Nov 26, 2007