ABSTRACT: Neisseria meningitidis causes invasive disease in 15 to 50 patients in British Columbia each year. However, recent data from Europe suggest that these figures may under-represent the true rate of disease by as much as 50%. New vaccines to prevent this disease have already been introduced in Europe and are likely to be licensed in North America within a few years. In order to inform future vaccine policy in Canada, improved surveillance for meningococcal disease is now needed. In this review we outline the recent epidemiology of meningococcal disease in British Columbia and describe access to a new service that is to be offered at Children’s and Women’s Health Centre, (BC’s Children’s Hospital) for molecular diagnosis of meningococcal infection. By reporting possible cases of meningococcal infection to local public health authorities, physicians and other primary-care providers play a pivotal role in enhanced meningococcal surveillance.
By reporting possible cases of meningococcal infection to local public health authorities, physicians and other primary-care providers play a pivotal role in enhanced meningococcal surveillance.
Between 15 and 50 cases of meningococcal infection are reported in British Columbia each year (Figure 1), with an overall mortality for the past 10 years of 8.5%, similar to the reported national rate for 1995–96 of 6.5%. This translates to a population incidence of 0.9/100,000 per year in BC, which is comparable to the national incidence in Canada and the USA.
The highest incidence of disease is in the winter months of the year, although cases may occur in any season. The disease usually presents as one of two clinical syndromes, namely meningitis and septicemia, or a combination of the two. Mortality is highest in those presenting with a predominant clinical picture of septicemia (shock, coagulopathy, multi-organ failure, and/or petechial rash) and estimated in children to be 25% in BC (personal communication, P. Skippen, pediatric intensive care unit, BC Children’s Hospital, 15 September 2000) and elsewhere.[3,4] Mortality in those presenting with clinical features of meningitis, without signs of shock, is approximately 5%.
Children under 5 years of age suffer the greatest burden of disease (Figure 2) with the peak incidence in most countries at 6 months to 2 years. An excess of disease is also noted in adolescents and young adults, and the increase in disease incidence in this age group in the US is greatest among college freshmen in dormitory accommodation. Sequelae including deafness, neurological deficits, and limb loss may occur in survivors.
Despite the dramatic presentation of invasive disease, Neisseria meningitidis harmlessly colonizes the nasopharynx of 10% to 25% of healthy adults at any point in time. Colonization is unusual in young children and increases through childhood to peak during the mid-teens.
In Canada, as in most other industrialized nations, meningococcal disease is endemic, and outbreaks only occur occasionally, representing very few of the overall number of cases. In 1999–2000 an outbreak of serogroup C disease occurred in Alberta involving 22 apparently unrelated cases, most patients aged 15 to 19 years. In response, the provincial government administered some 297,000 immunizations to persons 2 to 19 years old.
In contrast, huge epidemics of disease occur cyclically in Africa and Asia every 5 to 15 years[7-9] and epidemics were observed in North America after the Second World War, probably as a result of troops returning home with the disease. Travel may be an important factor in future epidemics and outbreaks too. Indeed, outbreaks occurred in 1989 and 2000, as pilgrims returned from the annual Hajj pilgrimage in Saudi Arabia, resulting in more than 330 cases worldwide in 2000.[10,11] However, epidemics are currently uncommon in industrialized nations.
Some risk factors for invasive meningococcal disease are established and include overcrowding, recent viral illness, tobacco smoking, passive exposure to tobacco smoke,[12,13] and complement deficiency.
Collection of surveillance data in British Columbia
Incidence data for meningococcal disease, as presented in Figure 1 and Figure 2, rely on passive laboratory notifications of culture-positive cases and physician notifications of probable cases. However, it seems that these data are incomplete. In addition to 22 laboratory-confirmed cases in 1999, there were six physician notifications of invasive meningococcal disease in BC that could not be laboratory confirmed. It is probable that other clinically suspicious cases of meningococcal disease may not have been reported for lack of laboratory confirmation. However, both proven and suspected cases of meningococcal disease should be reported.
The laboratory data may also be incomplete since Neisseria meningitidis can be difficult to isolate from clinical specimens, particularly when there is prior administration of antibiotics or a delay in delivery of specimens to a microbiology laboratory. In the United Kingdom, where molecular diagnosis is now widely used, it has been estimated that as many as 50% of cases are missed by use of conventional culture methods alone, suggesting that the actual incidence of invasive meningococcal disease in BC could range as high as 50 to 100 cases per year.
Serogroup and disease
The meningococcal serogroup is determined by the chemical composition of the polysaccharide that encapsulates the organism. Only five serogroups are commonly associated with disease, A, B, C, Y, and W135, though several others do cause occasional cases. Serogroup A causes epidemic and endemic disease in Africa and Asia. Serogroup B is the most prevalent serogroup associated with invasive disease in North America (including British Columbia, since 1997), while serogroup C is the usual cause of outbreaks of disease in Canada. The relative incidence of disease caused by the various serogroups varies over time, and a large increase in the proportion of cases caused by serogroup Y has been seen in the US in the past decade, though a similar temporal trend has not been observed in BC over this time. Serogroups A and W135 were linked to the recent Hajj outbreak.
Currently a polysaccharide vaccine against A, C, Y, and W135 meningococci is available in North America. This vaccine is used in the control of outbreaks, for persons with certain immunodeficiencies, and for travelers to epidemic zones, but for several reasons, it is not suitable for generating population immunity. First, it is poorly immunogenic in infants and young children. Second, it produces only short-lived immunity and does not seem to induce immunologic memory. Third, the vaccine does not cover the more common serogroup, B.
At present there is no federal strategy for preventing endemic meningococcal disease in Canada, although Alberta has recently offered vaccination for children and young adults aged 2 to 24 years in the Edmonton area in response to an outbreak. In the US, recent guidelines have been introduced that provide an opportunity for college freshmen to be vaccinated because of the increased risk of disease and outbreaks among these individuals. Unfortunately, this strategy has been estimated to offer protection against only a small proportion of all cases of meningococcal disease in the US and has low cost effectiveness.
New vaccines against meningococcal disease have recently been developed using the same technology as was adopted for the development of the Haemophilus influenzae type b (Hib) vaccine. These protein-polysaccharide conjugate vaccines are immunogenic in infancy and induce prolonged protection and immunologic memory. The first generation of such vaccines for meningococcal disease has been introduced in the United Kingdom. Implementation of a serogroup C conjugate vaccine program began in the fall of 1999 in the UK, aiming to vaccinate all individuals under the age of 20 years.
Infant immunization is now undertaken according to the UK accelerated vaccine schedule at 2, 3, and 4 months of age. Preliminary data demonstrated a 75% reduction in serogroup C disease in vaccinated children in early 2000, even before the catch-up campaign had been completed. Meningococcal vaccination of infants and children has now begun elsewhere in Europe. Combination A, C, Y, W135 protein-polysaccharide conjugate vaccines are also in development, and availability of mono and multivalent meningococcal conjugate vaccines in North America can be anticipated within a few years.
Today it has become even more important to have accurate surveillance data for meningococcal disease as this information will be essential to evaluate the need for and anticipated impact of the new vaccines. If these vaccines are eventually implemented in British Columbia, an enhanced meningococcal disease surveillance mechanism must be in place to ensure that the vaccines are effective and provide adequate coverage for the prevalent serogroups.
Of some concern is the fact that strain replacement has been observed for pneumococcal infections following use of the pneumococcal conjugate vaccine that has been recently licensed in the US. It is thought that this phenomenon arises because the vaccine prevents colonization and disease caused by the vaccine strain, thereby facilitating colonization by other strains. Since the new meningococcal vaccines will not include protection against serogroup B polysaccharide (the polysaccharide is a self-antigen for humans and is therefore poorly immunogenic), or rarer serogroups, it is possible that serogroup B or other strains would take up the ecological niche vacated by the vaccine serogroups.
Secondary cases of meningococcal disease may be prevented by providing chemoprophylaxis to contacts of cases (Figure 3). Household and kissing contacts of individuals presenting with meningococcal disease are as much as 1000 times more likely to develop disease than background population. Therefore, the physician who makes a clinical diagnosis of meningococcal disease has an important role in preventing secondary cases by offering chemoprophylaxis to available contacts and by informing the medical health officer from the local public health unit, who will arrange contact tracing.
Diagnosis of meningococcal disease
Laboratory confirmation of a clinical suspicion of meningococcal disease is usually not available for hours or days after presentation. This is not generally a problem for patients presenting with the characteristic petechial or purpuric rash of meningococcal disease and signs of meningitis or septicemia who will receive appropriate anti-microbial and emergency therapy as required (Figure 3). However, 20% of patients do not have the typical non-blanching rash: 7% have no rash and in 13% of patients the rash is maculopapular, making clinical diagnosis more difficult. Furthermore, 89% to 98% of patients presenting with a petechial rash do not have meningococcal disease at all.[26-28]
In individuals with meningococcal disease, lumbar puncture is often contraindicated because of shock, coagulopathy, or raised intracranial pressure, and current guidelines are moving away from recommending lumbar puncture at presentation because of the probable risk of deterioration in an unstable patient. Laboratory diagnosis is important for planning appropriate clinical management and public health measures (Figure 3).
Several methods for laboratory diagnosis of meningococcal disease are currently available, including conventional culture, latex agglutination tests, and polymerase chain reaction. Although laboratory sensitivity under field conditions for routine diagnosis of meningococcal disease is disappointing, case confirmation can be maximized by providing a combination of the available tests.
Microscopy and culture
In cases of meningococcal meningitis, microscopy of cerebrospinal fluid (CSF) may demonstrate the presence of Gram-negative diplococci and an elevated white cell count. Culture of blood, CSF, or fluid aspirated from skin lesions may all yield the diagnosis. However, meningococci may not grow readily in the laboratory, particularly if there has been a delay in specimen transport or handling or prior administration of antibiotics. Additionally, some strains grow poorly in automated blood culture systems. In one study of clinically suspected cases, sensitivity of culture was only 31%.
Latex antigen testing
Latex antigen testing of CSF or blood is used in many centres to aid in the diagnosis of meningococcal disease. This method of testing suffers from poor sensitivity, and although it may be improved by use of ultrasound enhancement, this technique has not been widely adopted.
The polymerase chain reaction
The polymerase chain reaction (PCR) is a highly sensitive technique for diagnosing meningococcal disease, with a 30% to 50% increase in case ascertainment noted in countries where this technique is now used to confirm clinical suspicion. A number of methods have been introduced for PCR diagnosis of meningococcal disease.[16,32-41] In this technique, bacterial DNA is isolated from blood or CSF and PCR is used to amplify a targeted gene that is specific to Neisseria meningitidis (Figure 4).
A detection system then identifies the presence or absence of the amplified product. The same technique can be used to identify the serogroup of the organism using the same specimen of isolated DNA, providing rapid, useful information for outbreak investigation. PCR is highly sensitive when evaluated using the gold standard of culture-confirmed cases. However, like conventional culture, PCR performs less well in detecting infection in clinically suspected cases, though still rather better than ordinary culture.
PCR diagnosis of meningococcal disease will be available in the Microbiology Laboratory at British Columbia’s Children’s Hospital (BCCH, Children’s and Women’s Health Centre of British Columbia) and is based on methodology developed in the United Kingdom at the Manchester Meningococcal Reference Laboratory. We have recently completed a laboratory study using this meningococcal PCR, which detects a capsular transferase gene (ctrA), and found a high degree of sensitivity and specificity (Pollard et al, unpublished observations, 2000). We also have the capability to provide serogroup information from the same samples using a second serogroup-specific PCR for serogroups B, C, Y, and W135.38,39 Implementation of this service has been undertaken in conjunction with the British Columbia Centre for Disease Control.
Physicians and microbiologists who have a clinical suspicion of meningococcal disease in a patient of any age are encouraged to send samples to the microbiology laboratory at BCCH (see Boxes 1, 2, and 3) for molecular diagnosis. Bacterial DNA can be extracted from blood or CSF, but whole blood is preferable to serum as some bacteria are lost in the fibrin clot during preparation of serum, resulting in a reduction in sensitivity. Blood samples should be collected as soon as possible after presentation of the patient, but PCR may be positive for more than 48 hours after initiation of antibiotic therapy.
Polymerase chain reaction for the presence of Neisseria meningitidis DNA will soon be routinely available within 5 working days and serogrouping will be undertaken monthly on positive samples. Since the emergency clinical management of a case of meningococcal disease is not usually dependent on diagnostic information, more rapid provision of PCR results will not be available initially. However, additional PCR runs will be undertaken when necessary to aid provincial epidemiologists in the linking of clusters of cases and in special circumstances.
Clinical microbiology laboratories should continue to send isolates of Neisseria meningitidis to the BC Centre for Disease Control Laboratory for serogrouping and further molecular typing.
In the next few years, there is the real possibility of preventing cases of meningococcal disease through immunization using new conjugate-protein meningococcal vaccines. Molecular diagnostics are now available and provide the opportunity for rapid and sensitive diagnosis of this disease, allowing better case ascertainment, facilitating outbreak investigation, and improving individual patient management. Through collaboration with physicians, microbiologists, and public health officials, BC’s Children’s Hospital and the BC Centre for Disease Control hope to provide the opportunity for achieving this goal in British Columbia using diagnostic polymerase chain reaction for Neisseria meningitidis.
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Dr Pollard is a Pediatric Infectious Disease Society clinical fellow in the Department of Pediatrics at the University of British Columbia (UBC), BC’s Children’s Hospital. Dr Bigham is a clinical assistant professor ain the Department of Health Care and Epidemiology at UBC and a physician-epidemiologist at the UBC Centre for Disease Control. Ms Shaw is the supervisor of the General Bacteriology Section of the BC Centre for Disease Control (BCCDC) Laboratory Services. Ms Bhachu is a research officer with Epidemiology Services, BCCDC. Dr Isaac-Renton is a professor of medical microbiology in the Department of Pathology and Laboratory Medicine at UBC and the director of Laboratory Services, BCCDC. Dr Tan is an assistant professor in the Department of Pathology and Laboratory Medicine, UBC, and a medical microbiologist at BC’s Children’s Hospital. Dr Thomas is a clinical associate professor in the Department of Pathology and Laboratory Medicine at UBC and head of the Microbiology, Virology, and Infection Control Program at the Children’s and Women’s Health Centre of British Columbia.
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