A Comprehensive Review on Meningococcal Meningitis

Introduction:

Meningitis is an inflammation of the meninges, the lining that protects the brain and spinal cord. It is almost always caused by an infection, usually by a bacteria (bacterial meningitis) or a virus (viral meningitis). In rare cases it can be triggered by a fungus or parasite. A number of bacterial agents can cause a severe and often fatal form of meningitis. The most common etiologies present today are Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. College-aged individuals are at increased risk for bacterial meningitis due to living conditions and social practices that facilitate pathogen

Nesseria meningitis:

N. meningitidis is a gram-negative encapsulated diplococcus. Approximately 12 strains of N. meningitidis exist and are characterized by the polysaccharide expressed on its capsule, A, B, C, 29-E, H, I, K, L, W-135, X, Y and Z. Serogroups A, B , C,Y and W-135 account for almost all the cases of the disease. Serogroups A, B and C cause 90% of meningococcal meningitis cases; while group B accounts for approximately half of these. The carbohydrate capsule of N. meningitidis determines its virulence and is targeted by the immune system. Meningococci of serogroup B, C, Y, W-135 express capsule composed of polysialic acid or sialic acid linked to glucose or galactose, while the capsule of group A N. meningitides is composed of N-acetyl mannosamine -1-phosphate.The development of a vaccine against serogroup B poses the biggest problem due to the similarity between the B capsular polysaccharide structure and a polysialic acid containing glycopeptides that are a part of human brain tissue. This similarity induces immunogenic tolerance to the B capsular coat.

Mode of infection: 

Neisseria meningitidis resides in its natural habitat within the nasopharyngeal tract of humans. 5-15% of the human population carries the bacteria in its nonpathogenic form. A major step in infection is its colonization in the nasophrynx of the human carrier. After colonizing the nasopharynx, the bacteria adhere to pili and cross the nasopharyngeal epithelium by a process of endocytosis to invade the circulatory system. In the bloodstream, the bacteria proliferate and adapt to the host environment. Clinical responses to infection are varied from a benign form to extreme, fatal forms (meningococcaemia). In its most severe form, heightened levels of bacteria in the blood make their way to the meninges in the brain and at such high levels of cytotoxicity, induce inflammation of the meninges and progression of the disease.

Disease epidemiology:

Meningococcal meningitis occurs sporadically worldwide and in focal epidemics. Meningococci are divided into distinct serogroups, according to their polysaccharide outer capsule. The most common serogroups that cause disease worldwide are groups B, C, A, Y and W135. It is the only form of bacterial meningitis that causes epidemics. Serogroups B and C are the most frequent causes of sporadic cases and outbreaks in Europe and the Americas. 1996 - 2000 figures, showed serogroup B accounted for 62% of all cases, group C (32%) and other groups including W135 & A (5%)

Notified cases of meningococcal disease; England & Wales Five Week moving average 1999/39 -2001/52.0

Rates* of Meningococcal Disease by Serogroup

• Per 100,000 population, CDC, ABC surveillance data

http://www.cdc.gov/ncidod/dbmd/abcs/survreports/mening03.pdf
Oregon data, DHS 2000-2004

Early clinical manifestations are often difficult to distinguish. Onset of the disease is rapid and the individuals are symptomatic for less than 24 hours. Even with administration of appropriate antimicrobials and other therapies. Approximately 11-19 % of meningococcal disease survivors have sequelae such as hearing loss and neurologic disability, or loss of skin, digits or limbs as a result of ischemia. Meningitis can kill up to 80% of infected patients if left untreated. It is also common cause of meningitis in children aged 2-18 with a mortality rate ranging from 4-40% and substantial morbidity in 11-19% of survivors. The traditional endemic, or hyperendemic, areas of the world (the "meningitis belt") include the savannah areas of sub-Saharan Africa extending from Gambia and Senegal in the west to Ethiopia and Western Eritrea in the east. This region can have a disease rate > 1,000 per 100,000 populations during epidemics.

Distribution of predominant N. meningitidis serogroups (A, B, C):

Serogroup A: Serogroup A has been the historically significant cause of meningitis epidemics worldwide. It is frequently responsible for infection in the Meningitis Belt, and has been documented as the cause of explosive epidemics in areas of the world as diverse as Brazil, North American, Finland, Nepal, and Saudi Arabia.

Image 1

Serogroup B: Serogroup B is associated with sporadic and isolated outbreaks of disease rather than widespread epidemics. Brief spikes in meningitis incidence in Oregon, Cuba, and Norway have been attributed to this serotype.

Serogroup C: Serogroup C, like Serogroup A, is another significant cause of epidemic meningitis. It has been responsible for epidemics in Brazil and Viet Nam , and is notable for its perpetual presence in the Meningitis Belt along with Serogroup A.

Image 2: Continental distribution of N. meningitidis serogroups A, B, C (1996-1997), From Tikhomirov E, Santa Maria M, Esteves K. Meningococcal disease: public health burden and control. World Health Stat Q 1997;50:171.

Image 3. Areas with frequent epidemics of meningococcal meningitis.

The number of cases due to serogroup W-135, which had only been responsible up until then for certain sporadic cases, has increased markedly. In 2001, a number of pilgrims returning from Mecca reported this disease in Asia, Europe and the United States . In 2002, a veritable epidemic affected Burkina Faso with 13,000 cases reported and 1400 deaths. Each year over two million Muslims from around the world gather in Mecca . All pilgrims to Hajj are required to show proof of vaccination against meningococcal meningitis A,C,W135,Y. This vaccine should have been received not more than three years and not less than ten days before arrival in Saudi Arabia, and should be recorded in a vaccination book showing the traveler’s full name. Vaccination is also a requirement for obtaining a visa.

Image 4:

However, the number of cases caused by serogroup C have significantly reduced since routine vaccination was introduced in those age groups targeted for vaccination (i.e. <18 year olds). In the first groups to be immunised, confirmed serogroup C meningococcal disease has been dramatically reduced by up to 90% in 15-17 year olds and 82% in infants under the age of one year.

Image 5:

Causes Of Meningitis:

The bacteria that cause meningococcal meningitis are widespread and live in the back of the nose and throat, or in the upper respiratory tract. The bacteria are spread among people by coughing, sneezing and kissing. These bacteria cannot live outside the body for long, so they cannot be picked up from water supplies, swimming pools, or a building's air-conditioning system. Individuals can carry these bacteria for days, weeks, or months without becoming ill. In fact, about 25 percent of the population carries the bacteria. Only rarely do the bacteria overcome the body's defenses and invade the cerebra spinal fluid, causing meningitis. The symptoms of meningitis are similar for both bacterial and viral forms of the disease.

Adults and older children typically experience:

Fever and chills, Headache ,Vomiting ,Stiff neck (patient may not be able to curl up in bed with nose to knees) ,Irritability and drowsiness ,Eyes that are sensitive to light ,Delirium and confusion (uncommon) ,Seizures (rare) ,Coma (rare)

Symptoms in infants and young children include:

Whimpering and crying in a high-pitched tone ,Difficulty in waking and very ,lethargic when awake ,Fussiness when being held or cuddled ,Arching the back and retracting the neck ,Staring blankly at their surroundings ,Having a high fever and cold hands and feet ,Refusing food ,Vomiting ,Appearing pale or blotchy . Meningococcal meningitis often causes a distinctive rash. This rash is the result of a form of septicemia (infection in the bloodstream), a potentially fatal condition.

Septicemia occurs when the meningococcal bacteria multiply uncontrollably in the bloodstream. The bacteria release toxins into the blood that break down the walls of the blood vessels, allowing blood to leak into the skin. The leaking causes a characteristic rash, called a hemorrhagic rash. The rash can appear anywhere on the body, including in the eyes and often between the toes. The rash starts as a cluster of tiny blood spots, which look like pin pricks in the skin. If untreated, these spots gradually grow and become multiple areas of bleeding, resembling fresh bruises under the skin surface. The spots or bruises do not blanch (turn white) when pressed

Diagnosis Of meingitis:

If meningitis is suspected, treatment should be sought immediately. At the hospital, a doctor can make a quick diagnosis by withdrawing a small sample of the spinal fluid (CSF) for examination. This procedure is called a lumbar puncture (spinal tap). It involves inserting a needle into the middle of the lower back and collecting some drops of fluid. The CSF is then examined under a microscope to look for bacteria or fungi. Normal CSF contains set percentages of glucose and protein. These percentages will vary with bacterial, viral, or other causes of meningitis. For example, bacterial meningitis causes a greatly lower than normal percentage of glucose to be present in CSF, as the bacteria are essentially "eating" the host's glucose, and using it for their own nutrition and energy production.

Normal CSF should contain no infection-fighting cells (white blood cells), so the presence of white blood cells in CSF is another indication of meningitis. Some of the withdrawn CSF is also put into special lab dishes to allow growth of the infecting organism, which can then be identified more easily. Special immunologic and serologic tests may also be used to help identify the infectious agent.

In rare instances, CSF from a lumbar puncture cannot be examined because the amount of swelling within the skull is so great that the pressure within the skull (intracranial pressure) is extremely high. This pressure is always measured immediately upon insertion of the LP needle. If it is found to be very high, no fluid is withdrawn because doing so could cause herniation of the brain stem. Herniation of the brain stem occurs when the part of the brain connecting to the spinal cord is thrust through the opening at the base of the skull into the spinal canal. Such herniation will cause compression of those structures within the brain stem that control the most vital functions of the body (breathing, heart beat, consciousness). Death or permanent debilitation follows herniation of the brain stem.

Laboratory analysis of the spinal fluid will confirm if the meninges are infected. The tests can usually, but not always, determine what type of germ has infected the patient. In newborns, doctors may also check the fluid in their stomach with a small tube passed down the throat, and test their feces for the presence of suspected germs.

Treatment Of meningits:

Doctors isolate patients with possible meningitis and immediately start them on intravenous antibiotics before they determine whether it's bacterial or viral meningitis.

Patients with bacterial meningitis receive intravenous antibiotics for a week or more. If the diagnosis turns out to be viral meningitis, the antibiotic treatment is stopped, because antibiotics have no effect on the viruses.

In the event that there is no vaccination available (for example, in cases of strain B meningococcal meningitis) people in close contact with the infected person are often given antibiotics such as rifampicin to keep them from acquiring the dangerous germ. Another antibiotic, ciprofloxacin, may be given to older children and adults.

Complications of Meningitis:

In general, nearly all people with viral meningitis and 70 to 80 percent of people with bacterial meningitis will recover, although that varies by age and health of the patient. Although most people make a swift and complete recovery, meningitis (particularly the bacterial form) can result in a variety of after effects. Some of these effects are permanent and physically disabling and some are less obvious, affecting the individual emotionally.

According to the National Meningitis Trust in England , infants and young children often face minor complications following meningitis. These include, Babyish behavior, Temper tantrums, forgetting recently learned skills, reverting to bed-wetting, Insomnia. Older children and adults may experience, Lethargy ,Recurring headaches ,Difficulty in concentration ,Short-term memory loss ,Clumsiness ,Balance problems ,Depression ,Bouts of aggression ,Mood swings ,Learning difficulties. Other serious complications can include, Brain damage, Epilepsy, Changes in eye sight

Prevention of Meningitis:

Apart from vaccination, there is no known way to protect against meningitis. Meningococcal meningitis prevented only through immunization. Meningococcal meningitis caused by strains A, C, Y and W135: The vaccine currently offers no protection against strain B, and it's effective for only 3 to 5 years.

It is recommended for all the people (unless pregnant), especially those ages 18 to 24.

People in close contact with individuals suffering from these strains of meningitis. People traveling to Africa or other parts of the world where these types of meningitis are prevalent. The vaccine is not very effective in small children.

The meningococcal vaccines currently approved for use in humans are made from the variant, purified capsular polysaccharides, which are characteristic of the bacteria membrane. Such vaccines are most effective against serogroups A and C although, in the United States, a quadrivalent vaccine containing four types of meningococcal bacteria (against serogroups A, C, Y, W-135) has proven to be 75-90% effective among people over two years of age. Of the population vaccinated, immunity has been shown to last approximately three years. With conjugation technology many types of monovalent or polyvalent vaccine are developed, where the polysaccharide of different serogroups are individually conjugated with Diphtheria toxoid or tetanus toxoid.

A protein based vaccine against serogroup B is also under development. In its endemic form meningococcal infection exhibits a predilection for children and adolescents with maximum incidence being seen in infants aged 3 to 12 months

Table: 1:Meningococcal vaccines and manufacturers:

References:

1. Characterization of Neisseria meningitidis isolates collected from 1974 to 2003 in Japan by multilocus sequence typing. Hideyuki Takahashi, Toshiro Kuroki, Yuko Watanabe, Hiroshi Tanaka, Hiroo Inouye, Shiro Yamai and Haruo Watanabe

2. The Neisseria meningitidis Capsule Is Important for Intracellular Survival in Human Cell s, Maria Rita Spinosa, Cinzia Progida, Adelfia Talà, Laura Cogli, Pietro Alifano, and Cecilia  Bucci. Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università degli Studi del Salento, Via Monteroni, 73100 Lecce, Italy

3.  Recognition of serogroup A Neisseria meningitidis serotype antigens by human antisera.  R J Sugasawara

4. Emergence of a virulent clone of Neisseria meningitidis serotype 2a that is associated with meningococcal group C disease in Canada . F E Ashton, J A Ryan, A Borczyk, D A Caugant, L Mancino, and D Huang, National Laboratory for Bacteriology, Laboratory Centre for Disease Control, Health and Welfare, Canada, Ottawa.

5.   Method of producing meningococcal meningitis vaccine for neisseria meningitidis serotypes a,c,y, and w-135. Wipo patent wo/2008/011201

6. An outer membrane protein of Neisseria meningitidis group b responsible for serotype  Specificity. Carl e. Frasch and Emil c. Gotschlich from the Rockefeller university, New York 10021. The Journal of Experimental Medicine, Vol 140, 87-104

7. Molecular Epidemiology of Neisseria meningitidis Isolated from Patients and Asymptomatic Carriers. Wantana Paveenkittiporn U-then Karnpakdee Pitimon Polwichai Siriporn Chantaroj and Surang Dejsirilert. National Institute of Health, Department of Medical Sciences,  Tiwanond Road, Nonthaburi 11000, Thailand .

8.  Picture areas with different epeide http://wwwn.cdc.gov/travel/yellowBookCh4-Menin.aspx

9.  Center for Disease Control and Prevention. Prevention and Control of Meningococcal Disease Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2005; 54 (No. RR-7 [12].

About Author:

Y. Srinivasulu

Currently working as Deputy Manager in Bacterial vaccines R&D, Biological E Ltd, Hyderabad, India. Previously worked in Shantha biotechnics limited for research on therapeutic drugs and vaccines, company located at Hyderabad, India. He has 8.5 years of experience in the biotechnology industry and presently working with the products like Haemophilus influenzae type b (Hib), Neisseria meningitidis vaccines.

He pursued M.Sc Micro-biology from Swami Ramanad Theerth Maratwada University, Nanded, India. During his post graduation he has done a research project on soil micro-flora at Soil science Department, ICRISAT (International Crops Research Institute for the Semi-Arid Tropics), Hyderabad, India. Presently I am doing PhD in biotechnology from Jawaharlal Nehru Technological University (JNTU), Hyderabad, India.

Currently he is working on his PhD in biotechnology from Jawaharlal Nehru Technological University (JNTU), Hyderabad, India.