Disease Name: Meningococcal disease Brijesh Singh Yadav brijeshbioinfo@gmail.

com Disease Type: Bacterial Disease Common Name: Meningococcal meningitis, Meningococcus Causative Agent: Neisseria meningitidis Disease Discription:Meningococcus is a serious bacterial infection caused by bacterium Neisseria meningitidis, known as a meningococcus causing severe illnesses like cerebrospinal meningitis (an infection of membranes that cover the brain & spinal cord) , septicaemia (blood poisoning) (1) . It is spread by person-to-person contact through respiratory droplets of infected people. There are 3 main clinical forms of the disease: the meningeal syndrome, the septic form and pneumonia. The onset of symptoms is sudden and death can follow within hours. In as many as 10-15% of survivors, there are persistent neurological defects, including hearing loss, speech disorders, and loss of limbs, mental retardation and paralysis. (3)

Fig .1 One of the stages of the distinctive meningococcal rash (bleeding into the skin) which can be a critical symptom of deadly septicemia (blood poisoning). (4) Causes of Disease: The meningococcus bacteria is spread by direct close contact with nose or throat discharge of an infected person. Many people carry this particular bacterium in their nose and throat without any signs of illness, while others may develop serious symptoms. When this blood-borne organism invades the cerebrospinal fluid, originating in the respiratory tract, the meningococcus bacteria travels, via the blood, into the cerebrospinal fluid (the watery liquid that surrounds the brain and spinal cord). During infection, the bacterium releases a toxin into the fluid causing an inflammatory reaction. If the bacteria invade the blood it can lead to arthritis, heart infections and pneumonia. If it damages the nerves leading into the brain it could cause hearing loss, learning disabilities, motor impairment or mental retardation.(13)

Risk Factors: Meningococcal disease can strike both children and adults – anywhere, at any time. But those most at risk are: • Babies and children up to the age of 5 years – this group accounts for two thirds of cases (due to their less mature immune system and tendency to put things in their mouth and share food, drink and toys). • Teenagers and young adults from 15 to 25 years – primarily because of the socially interactive lifestyle they lead, which is more likely to involve intimate activities such as kissing and sharing drinks. • Smoking and passive smoking – can increase the risk of infection. • Winter and early spring – are higher risk times, because the many viruses around can weaken the body’s natural immune system. There's also the risk of catching a virus first, followed a few days later by a meningococcal infection, making the illness much harder to identify. (4) Causative Agent Description: Pathogen Name: Neisseria meningitidis Pathogen Description: Neisseria meningitidis, also simply known as meningococcus, is a heterotrophic gram-negative diplococcal bacterium best known for its role in meningitis and other forms of meningococcal disease .It only infects humans; there is no animal reservoir. It is the only form of bacterial meningitis known to cause epidemics. Isolation: relatively fastidious; grows best on chocolate or Thayer-Martin agar; most strains grow on sheep blood but not non-enriched media Incubation: like most respiratory bacteria, N. meningitidis is capnophilic (has an affinity for CO2); 35oC in a 5% CO2 with high humidity is optimal. (8)

Taxonoimic Classification: Kingdom Phylum Class Order Family Genus Species Bacteria Proteobacteria Beta Proteobacteria Neisseriales Neisseriaceae Neisseria N. meningitidis

Fig.2 photomicrograph of Neisseria meningitidis (6)

There are many strains of meningococcus; the most clinically important are A, B, C, X, Y and W135:
• •

A - occurs most often in sub-sahara Africa and vaccination is recommended prior to travel with the Men A&C vaccine. B - is the most lethal form, comprising 40% of UK cases. The changing nature of the B group has prevented formation of a general B vaccine in the UK. However there has been developed the vaccine MeNZB against a specific strain of group B meningococcus, currently being used to control an epidemic in New Zealand. Previously, an earlier neisseria meningitidis vaccine against subtype B was not effective because the sialic acid residues of the capsule are similar to humans. C - caused approximately 60% of UK cases before the introduction of successful vaccination program for infants. Previously the unconjugated C component of Men A&C was ineffective in those under 2 years. The development of a conjugated form (Men C conj) was needed to provoke infant immunity. W135 - is particularly a problem for those undergoing annual pilgrimage to Mecca. It is a requirement of Saudi Arabia that all those intending to go on Hajj have a certificate of Men W135 vaccination. X - A large outbreak of meningitis caused by serogroup X was reported in Niger in 2006.This outbreak is particularly worrying because there is not currently any vaccine against this strain. Y - In the last decade serogroup Y has emerged as a cause of disease in Northern America

Other strains include 29-E, H, I, K, L, and Z.(7)

Other Pathogenic Sub species: Neisseria elongata ssp.nitroreducens, Neisseria gonorrhoeae, (11), N. cinerea, N. mucosa(subsp. Heidelbergensis, subsp. Mucosa) N. sicca, N. flavescens, N. subflava biovar subflava (9) Morphology and toxin production: CSF is usually very purulent (>1,000 PMN/micrometer) and the bacterium is usually intracellular; individual bacterial cells are kidney bean shaped; they appear in pairs with the flattened side of the “kidneys” adjacent to each other; it is gram-negative Colony morphology: 1-3mm, round smooth, convex, and moist to mucoid, grayish tan.

Species identification: N. meningitidis will not grow on blood or chocolate agar at room temperature nor on non-blood media at 35oC. (8)(9)

Fig.3 Gram Stain of CSF

Fig.4 Colonies on Chocolate agar

History: Description of illness resembling meningococcal disease dates back to the 16th century. Vieusseux described Meningococcal disease in 1805 during an outbreak with 33 deaths in the vicinity of Geneva, Switzerland. The Italian pathologists Marchiafava and Celli first described intracellular oval micrococci in a sample of CSF. The Italian pathologists Marchiafava and Celli (1884) first described intracellular oval micrococci in a sample of CSF. However, Anton Weichselbaum in 1887 first identified bacterium causing meningococcal disease in the CSF of six of eight patients of bacterial meningitis and the bacterium was named Neisseria intracellularis .

Before the 1920s, meningococcal disease was fatal in up to 70 percent of cases. Serum therapy with serum from immunized horses, introduced at the beginning of this century by Jochmann in Germany and Flexner in the United States, could reduce mortality from nearly 100% to 30%. The discovery of sulfonamides and other antimicrobial agents led to a further decline in case fatality rates. Despite treatment with appropriate antimicrobial agents and optimal medical care, the overall case fatality rates have remained relatively stable over the past 20 years, at 9 to 12%, with a rate of up to 40 % among patients with meningococcal sepsis. Eleven percent to 19% of survivors of meningococcal disease have sequelae, such as hearing loss, neurological disability, or loss of a limb.(2) Before the 1990s, Haemophilus influenzae type b (Hib) was the leading cause of bacterial meningitis, but new vaccines being given to all children as part of their routine immunizations have reduced the occurrence of invasive disease due to H. influenzae. Today, Streptococcus pneumoniae and Neisseria meningitidis are the leading causes of bacterial meningitis.(14) Epidemiology: Meningococcal infections occur worldwide as endemic disease. Epidemiological studies by modern molecular methods have disclosed a complex picture of a few pathogenic meningococcal clones spreading worldwide. It appears that the occurrence of invasive meningococcal disease is not determined solely by the introduction of a new virulent bacterial strain but also by other factors that enhance transmission. Of the five common serogroups (A, B, C, Y and W135) responsible for about 90% of infections caused by N. meningitidis; serogroups A, B and C account for most cases of meningococcal disease throughout the world, with serogroups A and C predominating throughout Asia and Africa and serogroups B and C responsible for the majority of cases in Europe and the Americas. In recent years, the number of cases involving serogroup Y has increased; from 1996 to 1998, one third of cases in United States were due to serogroup Y. Israel and Sweden are the only countries other than the United States that have reported an increase in serogroup Y disease. Serogroup W-135, currently accounting for only 4% of cases in the United States, was reported in 15 to 20% of isolates received by the Centers for Disease Control and Prevention between 1978 and 1980. In 2000, an international outbreak among pilgrims returning from the hajj (the pilgrimage to Mecca) and their close contacts, including four persons from the United States, was due to serogroup W135.Recently, serogroup W135 has been associated with an outbreak amongst Hajj pilgrims as well as a large epidemic in Burkina Faso during 2002 and 2003. caused outbreaks in Israel, the Czech Republic, Australia, England and Canada.There have been epidemics in Europe and in the Americas during the last 30 years, but they have not reached the very high incidence levels of epidemics as in other parts of the world. In the late 1970s, a serogroup B strain belonging to a clonal group known as ET-5 emerged, causing outbreaks in northwestern Europe and Central and South America. First

discovered in the Netherlands in 1980, strains belonging to another serogroup B clonal complex designated lineage III (ET-24 and ET-25) emerged in Europe. Serogroup B meningococcal disease caused 68% of cases reported in Europe between 1993 and 1996 and has also caused outbreaks in developed countries, with attack rates of 5 to 50 cases per 100,000 persons. The largest and most frequently recurring outbreaks have been in the semi-arid area of sub-Saharan Africa. In the African "meningitis belt," a region of savannah that extends from Ethiopia in the east to Senegal in the west, serogroup A meningococcal disease has posed a recurrent threat to public health for at least 100 years. In 1996, the largest outbreak ever reported occurred in the meningitis belt; the total number of cases reported to the World Health Organization (probably a substantial underestimate) was 152,813, with 15,783 deaths. The response to the epidemic by these countries exhausted international stocks of vaccine. Following large outbreaks in Africa in 1995-96, in 1997, the International Coordinating Group (ICG) for Vaccine Provision for Epidemic Meningitis Control was established. Main aims of ICG are to ensure rapid and equal access to vaccines, injection material and oily chloramphenicol and to ensure their adequate use when the stocks are limited. The ICG is composed of partners from the UN, including WHO, nongovernmental organizations, technical partners and the private sector. Asia has been focus of some major epidemics of meningococcal disease in the last 30 years (China 1979 and 1980, Vietnam 1977, Mongolia 1973-1974 and 1994-1995, Saudi Arabia 1987, Yemen 1988). Two clones of serogroup A caused the largest outbreaks, which originated in northern China and spread to the south and later globally. One of these clones spread to the Indian subcontinent in 1983 to 1987. Between 1987 to 1996, this clone traveled through the Middle East causing epidemic among pilgrims during the Haj in Mecca to African countries. In 1985, Bhutan was also hit by meningitis and 247 cases with 41 deaths were reported between September 1985 and March 1986.During 1982-1984, 1475 cases occurred in Kathmandu valley, Nepal, with highest mortality and morbidity in children less than one year of age. Serogroup B strains are common in developing countries. Most of these strains belong to a few clonal complexes; identified as ET-5, lineage III, cluster A4 and ET-37. Indian Scenario:Meningococcal disease is endemic in Delhi and sporadic cases of meningococcal meningitis have been occurring in Delhi in the past. Isolated cases of meningococcal meningitis during 1985 were also reported from several states of India including Haryana, Uttar Pradesh, Rajasthan, Sikkim, Gujarat, Jammu & Kashmir, West Bengal, Chandigarh, Kerala and Orissa. Serogroup A has been associated with all the repeated outbreaks of meningitis, although serogroup B and C have been detected in a few sporadic cases. An outbreak of pyogenic meningitis occurred in western part of India (Surat, Gujrat) during 1985-87.A total of 197 cases of meningitis with 34 deaths were reported during a period of one-and-a-half years. N. meningitidis was the predominant pathogen isolated from 66 out of 138 CSF samples. Recently migrated males of productive age groups

drawn from the States of Uttar Pradesh and Orissa were predominantly affected. Male to female ratio was found to be 7.2:1. Pregnancy and childbirth appeared to be important predisposing factors in females. Nine cases were reported from the family contacts of cases. Many outbreaks of meningococcal meningitis have been documented during 1966 and 1985 in Delhi and its adjoining areas. During 1966, 616 cases of meningitis were reported with case-fatality rate of 20.9%. The highest proportion of cases and deaths occurred in age group less than one year followed by that in 1-4 years. However, grouping of N. meningitidis could not be performed. A larger outbreak occurred in 1985 with greater number of cases than previous years and larger geographical area being affected. In early 2005, spurt of cases of meningoccemia and meningitis due to N. meningitidis serogroup A have been reported from Delhi and adjoining areas. As of June 17, 2005, 429 probable cases of meningococcal disease have been reported. Among these, 128 cases have revealed microbiological evidence (i.e, positive for direct microscopy/direct latex antigen detection/culture) of meningococci. Of these, 40 cases were culture positive for meningococci. The majority of cases and all deaths occurred in young adults between 16 -30 years of age. It is possible that the number of cases was in excess of the numbers notified. Clinically suspected cases of meningococcemia and meningococcal meningitis were being diagnosed and managed in almost all the major hospitals of Delhi and N. meningitidis serogroup A was isolated from a variable number of cases. Most of the reported cases were from the walled city of Old Delhi and Shahdara with a few cases being reported from the neighboring states of Uttar Pradesh and Haryana. The National Institute of Communicable Diseases (NICD) had been identified by Ministry of Health and Family Welfare as the nodal agency for investigation of this episode and provided laboratory support. The spurt of cases has waned off in late June 2005 but not completely disappeared.(2) Disease Host: Human Disease Transmission: The human naso-oropharyngeal mucosa is the only natural reservoir of N. meningitidis . Meningococci are transferred from one person to another by direct contact or via droplets. During periods of endemic infection, 8 to 20 % of adults are asymptomatic nasopharyngeal carriers of strains of N. meningitidis, most of which are not pathogenic. The carriage may be transient, intermittent, or persistant. Carriage strains may be encapsulated (groupable) or nonencapsulated (ungroupable). The carriage rate of meningococci is higher in lower socioeconomic classes, in military recruits, pilgrims, boarding-school students and prisoners. In households where a case of meningococcal disease has occurred, the risk of invasive disease in family members is increased by a factor of 400 to 800. The transmission rate of virulent clones is higher and invasive disease often occurs within the first week after acquisition, whereas some persons may carry pathogenic meningococci for many months or years without becoming ill. Various bacterial factors (virulence factors) as well as host factors influence the outcome of exposure to strains of N. meningitidis. (2)

Meningococcus is spread through the exchange of saliva and other respiratory secretions during activities like coughing, kissing, and chewing on toys. Though it initially produces with general symptoms like fatigue,it can rapidly progress from fever, headache and neck stiffness to coma and death. Death occurs in approximately 10% of cases. Mechanism: Rash on skin usually develops when the bacteria multiply in the blood vessels, and
release toxins, or poisons. These damage the blood vessels, so the blood can leak through into the tissues underneath the skin. It can start off either as a pink rash, or as tiny red or purple blood spots, like pin-pricks, anywhere on the body – which rapidly spread into purple blotches or bruises. The victim can literally bleed to death if not treated in time.

Fig.5 The bacteria leak poisons which damage the walls of the blood vessels, so the blood leaks into the skin – causing the rash. Signs and symptoms of disease: Symptoms in children and adults: A. Symptoms common to meningitis and septicemia: – fever (which may not go down with medication) – nausea or vomiting – lack of energy – tiredness or drowsiness – confusion or disorientation – dizziness – irritability or agitation – a sore throat B. Specific meningitis symptoms: – severe headache – backache – stiff or painful neck – sensitivity to light – twitching or convulsions

C. Specific septicemic symptoms: – fever with cold hands and feet – cold shivers – pain in muscles or joints – pain in chest or abdomen – pale, grey or blotchy skin – rapid breathing – diarrhoea – a rash, which may start off as a spot, scratch mark or blister, as a faint pink rash or as red or purple pinpricks on the skin, then develop into the distinctive purple bruising. Symptoms in babies – fever – fever with cold hands and feet – vomiting – diarrhoea – pale or blotchy skin – poor feeding – moaning/highpitched cry – blank, staring expression – dislike of being handled – fretful – floppy or lethargic – difficult to wake – arching of body/ neck – bulging fontanelle (soft spot on top of the head) – pink, red or purple rash (4) Diagnosis: A CSF specimen is sent to the laboratory immediately for identification of the organism. Diagnosis relies on culturing the organism on a chocolate agar plate. Further testing to differentiate the species includes testing for oxidase (all Neisseria show a positive reaction) and the carbohydrates maltose, sucrose,and glucose test in which N. meningitidis will oxidize (that is, utilize) the glucose and maltose. Serology determines the group of the isolated organism. Bacteriological diagnosis in patients with meningococcal disease is possible with a Gram stain, direct antigen detection using latex agglutination, or culture. Molecular diagnosis using polymerase chain reaction(PCR) has also been used.In patients with meningococcemia blood, skin lesion biopsy specimen, or CSF may be collected. In patients with meningococcal meningitis, skin lesions seldom reveal meningococci, blood cultures may not be always revealing and only CSF samples are generally positive. Non-selective chocolate agar and sheep blood agar should be used for recovery of N. meningitidis from CSF, blood and aspirates. Plates should be incubated in 5-7% CO 2 at 35 osub C and should be reported "no growth" only after 72 hours of examination. Suspected colonies of N. meningitidis are gray colored, about 1mm diameter, low convex,

with smooth moist entire edge and glistening surface. The medium beneath and adjacent to the colonies may exhibit a gray green cast, particularly in areas of confluent growth. From growth on a blood agar plate, Kovac's oxidase test should be performed and then the serogroup should be identified. Finally, carbohydrate utilization tests should be used for confirmation of isolates as N. meningitidis Treatment: A range of antibiotics may be used for treatment including penicillin, ampicillin, chloramphenicol, and ceftriaxone. (3) Other treatments may include:
• • • •

Intravenous fluids to treat shock and prevent organ damage Medications such as noradrenaline (nor epinephrine) for patients with very low blood pressure Blood products such as platelets and fresh frozen plasma Oxygen and ventilation by a machine to assist with breathing (12)

Prevention: One is by immunisation with vaccines (immunoprophylaxis) and the other is giving antibiotic therapy to close contacts of patients with meningococcal disease (antimicrobial chemo prophylaxis). Antibiotic therapy o It is recommended for close contacts of patients with meningococcal disease like household members, childcare centre contacts, anyone exposed to infected respiratory secretions o Start treatment as soon as possible since the rate of disease in close contacts is highest during the first few days after the onset of disease in the original case. o Antibiotics used include rifampicin, ciprofloxacin, and ceftriaxone. Immunisation by vaccination o Immunisation with meningococcal vaccine is not routinely done because of its relative ineffectiveness in children <2 years and its short duration of protection (approximately 3 years). o There is a new vaccine currently being developed which may be more effective than the existing vaccines. o Meningococcal vaccine is currently only used for high-risk groups, these include asplenic individuals, individuals with complement deficiencies, individuals travelling to countries where the incidence of meningococcal infections is high, military recruits (in US) (12)

Source : MEDWORK

Fig.6 Worldwide distribution of Meningococcal disease

Geographical Distribution: Meningococcal meningitis occurs sporadically in small clusters throughout the world with seasonal variations and accounts for a variable proportion of endemic bacterial meningitis. In temperate regions the number of cases increases in winter and spring. Serogroups B and C together account for a large majority of cases in Europe and the Americas. Several local outbreaks due to N. meningitidis serogroup C have been reported in Canada and USA (1992-93) and in Spain (1995-97). For 10 years, the meningococcal meningitis activity has particularly increased in New Zealand where an average of 500 cases occurs every year. Most of these cases are now due to serogroup B. Major African epidemics are associated with N. meningitidis serogroups A and C and serogroup A is usually the cause of meningococcal disease in Asia. Outside Africa, only Mongolia reported a large epidemic in the recent years (1994-95). There is increasing evidence of serogroup W135 being associated with outbreaks of considerable size. In 2000 and 2001 several hundred pilgrims attending the Hajj in Saudia Arabia were infected with N. meningitidis W135. Then in 2002, W135 emerged in Burkina Faso, striking 13,000 people and killing 1,500. The highest burden of meningococcal disease occurs in sub-Saharan Africa, which is known as the “Meningitis Belt”, an area that stretches from Senegal in the west to Ethiopia in the east, with an estimated total population of 300 million people. This hyperendemic area is characterized by particular climate and social habits. During the dry season, between December and June, because of dust winds and upper respiratory tract infections due to cold nights, the local immunity of the pharynx is diminished increasing the risk of meningitis. At the same time, the transmission of N. meningitidis is favoured

by overcrowded

housing at family level and by large population displacements due to pilgrimages and traditional markets at regional level. (3)

Fig.7: African meningitis belt Disease Statistics: I. In the United States, increased frequency of serogroups B and Y meningococci has been noted since 1990. The frequency of localized outbreaks has increased since 1991. II. In one study conducted in the United States, males accounted for 55% of total cases of meningococcal meningitis. III. Meningococcal meningitis most commonly affects individuals aged between 3 years and adolescence. It rarely occurs in individuals older than 50 years.(15) IV. About 3000 people in the United States get this disease each year, and 1 in 10 of them die from it. V. As deadly as meningococcal disease can be, most cases in the United States (up to 83 percent of cases in adolescents and young adults) could potentially be prevented by a single vaccination.

Incidence of Meningococcal Disease by Serogroup and Year(10)
Fig. 8

Fig.9: Notified cases of meningococcal disease by race and sex, South Africa, 2003. Source: NDOH, Health Systems Research, Research Coordination and Epidemiology Fig.10 In Canada, there are three predominant groups (all causing the same disease).

Fig.11 In Australia, Group B is dominant. There is no vaccination yet available for Group B, although there is now one for Group C.

Text source: 1. Ministry of Health –new Zealand 2. Indian journal of medical microbiology 3. WHO

4. 5. 6. 7.

Meningococcal education Centers for Disease Control and Prevention, USA
Sherris Medical Microbiology, 4th ed., McGraw Hill, 329–333

Boisier P, Nicolas P, Djibo S, et al. (2007). "Meningococcal Meningitis: Unprecedented Incidence of Serogroup X–Related Cases in 2006 in Niger”. Clin Infect Dis 44: 657–63. doi:10.1086/511646. 8. http://campuspages.cvcc.vccs.edu/BIO_Rhoads/Bacteriology/leftover %20PPT%20per%20body%20system/MDL%20237%20Pathogens%20in %20Central%20Nervous%20System.ppt. 9. Centres for disease control & Prevention , Dept of Health & human services. 10. The Journal of the American Medical Association 11. Journal article from SpringerLink 12. New Zealand Dermatological Society 13. USA Today 14. McKinley Health Centre 15. eMedicine

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