What is meningococcemia?

Meningococcemia is a bacterial infection of the blood due to Neisseria meningitidis. This bacterium is most famous for causing meningococcal meningitis which may also be present in meningococcemia. Bloodstream infections are sometimes called "blood poisoning" or septicemia. Many bacteria can cause bloodstream infections including staphylococci, Streptococcus B, or Streptococcus A. In addition, other bacteria can cause meningitis, including Streptococcus pneumoniae or leptospirosis. However,N. meningitidis is concerning because it is more contagious than these other bacteria and typically infects older children and adolescents.

Picture of Neisseria meningitidis seen under the microscope; SOURCE: CDC/Dr. Brodsky

Pathophysiology
Humans are the only known reservoir of N meningitis and can transmit the organisms by aerosols or nasopharyngeal secretions. Meningococcal infection is preceded by nasopharyngeal colonization. Attachment to the nasopharyngeal epithelial cells is aided by meningococci-expressed pili, such as the type IV pilus encoded by pilC, which binds to human cell surface protein CD46. Meningococci then enter the bloodstream and spread to specific sites, such as the meninges or joints, or disseminate throughout the body. Five percent of individuals become long-term carriers, most of whom are asymptomatic. In outbreaks, the carriage rate of an epidemic strain can reach 90%. Intimate contacts of individuals with meningococcemia are 100-1000 times more likely than normal to acquire infection. 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,[2] as follows:

A polysaccharide capsule (which also determines the serogroup) enables the organism to resist phagocytosis.[3] A lipo-oligosaccharide endotoxin (LOS) can be shed in large amounts by a process called blebbing, causing fever, shock, and other pathophysiology. This is considered the principal factor that produces the high endotoxin levels in meningococcal sepsis. Meningococcal LOS interacts with human cells, producing proinflammatory cytokines and chemokines, including interleukin 1 (IL-1), IL-6, and tumor necrosis factor (TNF). LOS is one of the important structures that mediate meningococcal attachment to and invasion into epithelial cells.[4] An immunoglobulin A1 protease cleaves lysosomal membrane glycoprotein-1 (LAMP1), helping the organism to survive intracellularly. Individuals with immunity against meningococcal infections have bactericidal antibodies against cell wall antigens and capsular polysaccharide. A deficiency of circulating antimeningococcal antibodies is associated with disease. 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.

EPIDEMIOLOGY:

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, an increase in serogroup Y disease was noted in the 1990s. An outbreak of meningococcal disease is defined as 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 of meningococcal disease and attributed deaths rose in 1995, due mainly to serogroup C disease. This declined when serogroup C conjugate vaccine was introduced in the national immunization program. [5] For more than a century, serogroup A meningococcal disease has been endemic in the African Meningitis Belt, which extends from Ethiopia in eastern Africa to Senegal in West Africa.

Outbreaks of meningococcal disease occurred during the annual hajj (pilgrimage) in Saudi Arabia in 2000 and 2001 among pilgrims and household contacts.[6, 7] 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 also occasionally reported in the United States. Meningococcal disease may be a significant but under-reported problem in developing Asian countries.[8] Serogroup W-135 has been associated with pilgrims returning from the hajj. [6, 9] 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%. Nosocomial transmission to patient care personnel and laboratory staff is rare.

Mortality/Morbidity

The mortality rate of fulminant infection remains high, with most deaths occurring within 48 hours. Half of all patients with shock who die do so within the first 12 hours of hospitalization. [10] In industrialized countries, the mortality rate can exceed 40%; 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
Meningococcal disease is somewhat more prevalent in males (1.2 cases per 100,000) than in females (1 case per 100,000).

Age

In epidemics of meningococcal disease, people of any age may be affected, with the case distribution shifted toward older individuals. Endemic meningococcal disease is most common in children aged 6-36 months. Children younger than 6 months are protected by maternal antibodies. In New York City, from 19892000, 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.[11] Occult meningococcemia is an uncommon form of infection that affects children aged 3-24 months.

What causes meningococcemia?

As mentioned, the bacterium that causes meningococcemia is called N. meningitidis, also known as "meningococcus." Meningococcemia may also be called meningococcal

bacteremia. Under the microscope, the bacteria may appear in pairs, looking like two small kidney beans side by side. N. meningitidis is surrounded by a capsule made of complex carbohydrates called polysaccharides. These polysaccharides stimulate the immune system, which helps the body fight the infection. There are several different types (serogroups) of meningococci. Most human disease is caused by serogroups A, B, C, Y, and W135. Bacteria from other serogroups are called "nonpathogenic," meaning that they do not cause disease. Transmission of N. meningitidis is from person to person through respiratory secretions. Some people can harbor the bacteria in their throats and not get sick, which is called a "carrier" state. In others, the bacteria rapidly invade the tissues and bloodstream, causing disease.

What are risk factors for meningococcemia?

Children and adolescents 5 to 19 years of age are at highest risk for meningococcemia. Newborns acquire antibodies from their mothers via the placenta, although these antibodies fade after a few weeks or months.Toddlers are not immune, and there have been several exposures in day-care settings. As children age, they gradually gain immunity to meningococcal strains by coming into contact with milder strains of the bacteria. However, because this immunity is imperfect, it is still possible for adults to get meningococcemia. The immune system is critical in fighting off the bacteria. Patients who have a history of a specific genetic deficiency in the complement system are at high risk for severe disease. The spleen is also needed for an effective immune response, so people are at higher risk for severe disease if they have had their spleens taken out or have spleens that function poorly. People who have been in close contact with an infected patient are at increased risk to acquire the disease themselves. People who live together in close quarters such as military barracks are at especial risk for disease. One study showed that the attack rate in household contacts was 500 times greater than that of the general population. In some parts of the world, outbreaks of meningococcal disease occur regularly. This is true of a group of countries in sub-Saharan Africa, which is known as the "meningitis belt." Because travelers from this area visit Saudi Arabia during the Hajj, there have been outbreaks associated with the pilgrimage. Saudi Arabia now requires proof of vaccination before admitting pilgrims.

What are symptoms and signs of meningococcemia?

After an average incubation period of three to seven days (range one to 10 days), infected patients initially experience fatigue, fever, headache, and body aches, similar to those experienced by people with influenza, including swine flu or bird flu. Shaking chillsmay be present. Rash is common and appears like small red dots (petechiae) associated with low platelet counts or a bleed into the skin (purpura) associated withvasculitis. The rash may appear anywhere on the body, even on the palms or soles or inside the mouth. In addition to the rash, physical examination reveals a fast heart rate and often a low blood pressure and other signs of shock. Laboratory examination shows increases in white blood cell counts and may show low platelet counts (thrombocytopenia). The bacteria may spread to the heart, causingmyocarditis. In severe cases, multiple organ systems may fail, including the kidneys, lungs and airways, liver, or heart. Uncommonly, the bacteria may cause a low-grade bloodstream infection (chronic meningococcemia) with fever, joint pain, and rash that lasts one to three weeks. Although meningococcemia refers to an infection of the bloodstream, it is important to note that some patients with meningococcemia will develop meningococcal meningitis. Meningococcemia poses a higher risk of shock and death than meningococcal meningitis. Thus, although they are defined differently and have different prognoses, there is significant overlap between meningococcemia and meningococcal meningitis.

How is meningococcemia diagnosed?

Patients are often presumptively diagnosed with meningococcemia from the patient's history and physical exam, but a definitive diagnosis is usually sought. This presumptive diagnosis is important because treatment needs to be started as soon as possible if meningococcemia is suspected. Meningococcemia is diagnosed by culturingN. meningitidis from a sample of blood. The bacteria grow in one to two days in most cases, and biochemical methods are used to identify them as N. meningitidis. Samples of the growth can also be stained and examined under the microscope to detect the characteristic double kidney bean appearance of the bacteria, although the biochemical tests are needed for definitive diagnosis. In some instances, skin scrapings from pustular lesions can reveal the organisms; other investigators have occasionally used aPCR test to detect N. meningitidis.

What is the treatment for meningococcemia?

Intravenous antibiotics are needed to treat meningococcemia. Most strains remain sensitive to older treatments such as ampicillin (Omnipen, Polycillin, Principen) or penicillin G (Bicillin L-A), although a few strains are resistant and require therapy with a newer agent such as ceftriaxone (Rocephin). The laboratory will test the bacteria to see which antibiotics will work best, but treatment will need to start before the results of these antimicrobial sensitivity tests come back. Therefore, doctors usually select antibiotics that are known to work against most strains of N. meningitidis. Blood pressure is supported with intravenous fluids or medications. Meningococcemia often requires treatment in an intensive-care unit. Recently, a newer agent called drotrecogin alpha (Xigris) has shown some efficacy in reducing complications of severe bloodstream infections, although only a small number of patients with meningococcemia have been tested. This agent has the potential to cause serious bleeding, so it should not be used in patients who are already at increased risk for bleeding. Thus, use of drotrecogin alpha remains controversial.

Meningococcemia

Meningococcemia is an acute and potentially life-threatening infection of the bloodstream. See also: Septicemia Causes Meningococcemia is caused by a bacteria called Neisseria meningitidis. The bacteria frequently lives in a person's upper respiratory tract without causing visible signs of illness. The bacteria can be spread from person to person through respiratory droplets -- for example, you may become infected if you are around someone with the condition when they sneeze or cough.

Family members and those closely exposed to someone with the condition are at increased risk. The infection occurs more frequently in winter and early spring. Symptoms There may be few symptoms at first. Some may include:

Anxiety Fever Headache Irritability Muscle pain Nausea Rash with red or purple spots (petechiae)

Later symptoms may include:

Changing level of consciousness Large areas of bleeding under the skin (purpura) Shock

Exams and Tests Blood tests will be done to rule out other infections and help confirm meningococcemia. Such tests may include:

Blood culture Complete blood count with differential Clotting studies (PT, PTT)

Other tests that may be done include:

Lumbar puncture to obtain spinal fluid sample for CSF culture Skin biopsy and gram stain Urinalysis

Treatment Meningococcemia is a medical emergency. Persons with this type of infection are often admitted to the intensive care unit of the hospital, where they are closely monitored. The person may be placed in respiratory isolation for the first 24 hours to help prevent the spread of the infection to others.

Treatments may include:

Antibiotics given through a vein (IV), given immediately Breathing support Clotting factors or platelet replacement -- if bleeding disorders develop Fluids through a vein (IV) Medications to treat low blood pressure Wound care for areas of skin with blood clots

Outlook (Prognosis) Early treatment results in a good outcome. When shock develops, the outcome is less certain. The condition is most life threatening in those who have:

Disseminated intravascular coagulopathy (DIC) - a severe bleeding disorder Kidney failure Shock

Patients who do not develop meningitis also tend to have a poorer outcome. Possible Complications

Arthritis Disseminated intravascular coagulopathy (DIC) Gangrene due to lack of blood supply Inflammation of blood vessels in the skin (cutaneous vasculitis) Myocarditis Pericarditis Shock Severe damage to adrenal glands that can lead to low blood pressure (WaterhouseFriderichsen syndrome)

When to Contact a Medical Professional Go to the emergency room immediately if you have symptoms of meningococcemia. Call your doctor if you have been around someone with the disease. Prevention Preventive antibiotics for family members and contacts are often recommended. Speak with your health care provider about this option.

A vaccine that covers some -- but not all -- strains of meningococcus is recommended for children. Unvaccinated college students who live in dormitories should also consider receiving this vaccine. In this scenario, it should be given a few weeks before they first move into the dormitory. You should discuss the appropriate use of this vaccine with your health care provider. Alternative Names Meningococcal septicemia; Meningococcal blood poisoning; Meningococcal bacteremia

Meningococcemia Meningococcal infection is brought by the bacteria Neisseria meningitides. Meningococcemia is an abnormal condition characterized by the presence of meningococci in the blood. The most common form of disease due to meningococcal infection is meningitis and the less common is Meningococcemia. What is Meningococcemia? Meningococcemia is a clinical form brought about by spread of the bacteria (Neisseria meningitides) to the bloodstream causing severe signs and symptoms. The most devastating form of meningococcemia is fulminant meningococcemia which consists of hemorrhagic rashes, drop in blood pressure and circulating shock leading to death. How does meningococcal disease spread? Infection is spread by direct contact with discharges from the nose and throat which contain the bacteria. Although meningococcal bacteria are common, they are extremely delicate outside of the body and are not very contagious. The bacteria spread from an infected carrier to another person through close, direct physical contact and through coughing, and sneezing, kissing. It can also spread

through saliva (spit) when sharing items such as food or drinks, cups, utensils and drinking straws. In general, people should not share anything that has been in their mouth. Exposure to cigarette smoke increases the risk of spread of meningococci, as well as other bacteria. Signs and Symptoms:

fever stiff neck convulsion, in some delirium altered mental status vomiting cough, sore throat, other respiratory symptoms pinpoint rashes then become wider and appear like bruises starting on the legs and arms large map like bruise-like patches severe skin lesions may lead to gangrene unstable vital signs may or may not have signs of meningitis such as:

- stiff neck - convulsion - delirium - altered mental status - vomiting Who is considered a close contact of a meningococcal disease? A close contact is someone who is likely to have had direct contact with saliva or mucous from the nose or throat of an infected person.

those who live in the same house those who have kissed the infected person those who share a bed children in the same childcare center or nursery because they frequently put objects into their mouths those who share drinks, cigarettes, food, drinks, water, glasses,

cups, lipstick, musical instruments with mouthpieces, or anything else that has been in the mouth of the infected person

What happens when someone is a close contact?

Close contacts of a case of meningococcal disease may be given an antibiotic to protect them. Classmates or co-workers of an infected person are not considered to be close contacts unless they have had direct contact with secretions from the mouth or nose of the sick person. Those who are close contacts of the infected person do not pose a risk to others and may continue to attend school or work. Siblings and other family members of close contacts do not require preventive treatment. In most cases, classes, school-related or work- related activities will continue as planned. Depending on the circumstances, public health officials may recommend that close contacts receive antibiotics, vaccine, or both in order to prevent additional cases of meningococcal disease.

Can meningococcemia and meningitis be treated? Penicillin kills meningococcal bacteria that have invaded the body. Early recognition of meningococcal infection and prompt treatment with penicillin greatly improves chances of survival. How does one prevent meningococcemia?

Wash hands frequently with soap and water. Avoid close contact with meningococcemia patients. Increase resistance by having healthy diet, regular exercise, adequate rest and sleep, no alcohol and cigarette smoking. Maintain clean environment/surroundings Don't share utensils, cups, water bottles, lipstick, cigarettes and other water bottles, dishes, glasses, cups, lipstick, musical instruments with mouthpieces, mouth guards, or anything else that has been in the mouth of the infected person Avoid crowded places.

History
Persons with meningococcal disease may present with a nonspecific prodrome of cough, headache, and sore throat. 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. See an example shown below.

Petechial lesions on the palm. Courtesy of Professor Chien Liu.

Meningitis that accompanies meningococcemia may result in headache, neck stiffness, lethargy, and drowsiness. 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 (rare), painful skin lesions are present on the extremities (see the following images), similar to those seen ingonococcemia, with migratory polyarthritis and tenosynovitis. Antibiotic treatment results in a prompt response.

Petechial rash on lower extremities. Courtesy of Professor Chien Liu.

Petechial lesions on the palm. Courtesy of Professor Chien Liu.

Physical

Patients with meningococcal disease appear severely ill.

Tachycardia and mild hypotension are present. Fever is moderate. High fever is present in fulminant meningococcemia. A petechial rash develops in 50-80% of patients and involves the axillae, flanks, wrists, and ankles as shown in the images below. 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. They are discrete lesions 1-2 mm in diameter. Confluence of lesions

results in hemorrhagic patches, often with central necrosis.

Dorsum of the hand showing a petechial rash. Courtesy of Professor Chien Liu.

Petechial rash on lower extremities. Courtesy of Professor Chien Liu.

In some cases, a transient maculopapular rash develops, usually lasting for less than 48 hours.[12] Congestive heart failure, gallops, and pulmonary edema may be present. Other evidence of end-organ damage may also rapidly appear. Patients with fulminant meningococcemia rapidly deteriorate clinically, with hypotension and respiratory failure. Pericarditis can occur during the acute disease or in the recovery period and is associated with serogroup C disease.

Causes:

Meningococci (0.6 m X 0.8 m) are gram-negative single cocci or diplococci (see the image below) with flattened adjacent sides. Older cultures can vary considerably in size and shape. Serotyping is based on the polysaccharide capsule. The organisms grow at 35-37C in a moist oxygen-reduced atmosphere containing 5-19% carbon dioxide on media that contains blood.

Gram-negative intracellular diplococci. Courtesy Professor Chien Liu.

Seroagglutination is used to 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 are at an increased risk for meningococcal infections. Recurrent meningococcemia has also been reported in patients with immunoglobulin G2 subclass deficiency. Splenectomy and host genetic polymorphisms are also risk factors.

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

Promptly begin antibiotic treatment. Suspect fulminant meningococcemia in patient with hypotension and severe coagulation abnormalities. In such cases, monitoring in an intensive care setting is required. Other than antimicrobial treatment, supportive measures may be needed to correct circulatory collapse. Any adrenal insufficiency requires corticosteroid replacement.