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Vaccine preventable meningitis in Malaysia: epidemiology and management Expert Rev. Anti Infect. Ther. 13(6), 705–714 (2015)
Hannah C McNeil1, Johanna MC Jefferies2 and Stuart C Clarke*1,2 1 University of Southampton Malaysia Campus, No.3, Persiaran Canselor 1, Kota Ilmu, Educity, Iskandar, 79200 Nusajaya, Johor, Malaysia 2 Faculty of Medicine and Institute of Life Sciences, University of Southampton, Southampton, UK *Author for correspondence: Tel.: +60 7560 2469 [email protected]
Worldwide bacterial meningitis accounts for more than one million cases and 135,000 deaths annually. Profound, lasting neurological complications occur in 9–25% of cases. This review confirms the greatest risk from bacterial meningitis is in early life in Malaysia. Much of the disease burden can be avoided by immunization, particularly against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae. Despite inclusion of the Hib vaccine in the National Immunisation Programme and the licensure of pneumococcal vaccines, these two species are the main contributors to bacterial meningitis in Malaysia, with Neisseria meningitidis and Mycobacterium tuberculosis, causing a smaller proportion of disease. The high Hib prevalence may partly be due to dated, small-scale studies limiting the understanding of the current epidemiological situation. This highlights the need for larger, better quality surveillance from Malaysia to evaluate the success of Hib immunization and to help guide immunization policy for vaccines against S. pneumoniae and N. meningitidis. KEYWORDS: etiology . disease surveillance . Haemophilus influenzae . immunization . Malaysia . meningitis .
Mycobacterium tuberculosis
.
Neisseria meningitides . Streptococcus pneumoniae
Bacterial meningitis remains a devastating disease, accounting for at least 1.2 million cases and 135,000 deaths worldwide annually, excluding epidemics [1]. Depending on WHO region, bacterial meningitis leaves 9–25% of survivors with serious and burdensome postdischarge sequelae, including neurological damage, epilepsy, hearing loss, amputation and delayed development. Children under 5 years of age are disproportionately affected [2]. Highly immunogenic conjugate vaccines that induce long-lasting protection are available against the major causes of bacterial meningitis, namely Haemophilus influenzae serotype b (Hib), Streptococcus pneumoniae and Neisseria meningitidis. However, only the Hib vaccine has been added to the National Immunisation Programme (NIP) in Malaysia. There is a wealth of epidemiologic data on the success of immunization programmes in reducing the incidence of meningitis and consequential mortality and morbidity associated with Hib, N. meningitidis and S. pneumoniae, where such vaccination programmes have been informahealthcare.com
10.1586/14787210.2015.1033401
introduced, both in developed and in developing countries [3–6]. Such data for Malaysia are scarcer and sporadic, especially considering its status as an upper middle-income country [7], where health care is heavily subsidized and no one is refused treatment on the basis of an inability to pay [8]. Reviews frequently focus on the burden of meningitis attributable to a single causative organism rather than highlighting the overall disease burden of meningitis. As much of the disease burden of bacterial meningitis is vaccine preventable, this review seeks to collate information in the public domain on potentially avoidable meningitis in Malaysia and obtain a clearer view of burden by etiology. Method
This review seeks to summarize information relevant to the epidemiology and management of vaccine preventable bacterial meningitis for Malaysia, in English language peer-reviewed journals, published since 1980. A literature search was undertaken using PubMed, where
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Table 1. Summary of studies into multiple etiologies of meningitis in Malaysia. Study period
Focus of study
Location
Age group
% cases etiology identified, (n)
Case fatality rate
Ref.
Jan 1983–June 1986
All causes of pediatric meningitis
Single centre, Sabah†
Neonate to 70 years
100% (47)
7/47 (15%)
[13]
[9]
†
Sandakan, Duchess of Kent Hospital. Includes one fungal and 3 viral cases. Hospital Universiti Sains Malaysia, the only tertiary centre serving this rural state for pediatric referrals during study period. ¶ Nenonates specifically excluded from study. # Positive laboratory speciation of agent required for study inclusion. †† TB specifically excluded from study. ‡‡ Pediatric Institute, Kuala Lumpur Hospital. §§ 10 viral cases. ¶¶ Pediatric Institute, Hospital Kuala Lumpur, Kota Bahru Hospital, Kelantan, Hospital Sultanah Aminah, Johor, Hospital Alor Setar, Kedah and Hospital Kuching, Sarawak. ## Number of laboratory confirmed cases of meningitis. ††† Number of cases symptomatic of meningitis. ‡‡‡ University of Malaya Medical Centre. ‡ §
the search for terms was limited to the article title and abstract. Primary search terms included ‘Malaysia’ and ‘bacterial meningitis’. In PubMed the MeSH term ‘bacterial meningitis’ encompasses the following categories; ‘Meningitis, Escherichia coli’, ‘Meningitis, Haemophilus’, ‘Meningitis, Listeria’, ‘Meningitis, Meningococcal’, ‘Meningitis, Pneumococcal’, and ‘Tuberculosis, Meningeal’ and sub-categories thereof. The searches above were repeated with the term, ‘Malaysia’ replaced with ‘Asia’. Additional information came from citations used by articles from the PubMed search. For the purposes of this review, a case of meningitis, or the laboratory definition of meningitis, was accepted as defined by the study’s author(s). Cases of, and studies into, noninfectious, viral, fungal, parasitic meningitis, nontyphoidal salmonellosis, Klebsiella, Staphylococcus aureus, E. coli and Listeria were excluded, except where the findings for these causes of meningitis were inextricably included in the overall findings for studies of multiple etiology. Also excluded were references where the focus was on sampling and diagnostic methods, serotyping methods, nosocomially acquired meningitis, animal meningitis, antimicrobial resistance and drug trials.
Findings: overall meningitis burden of mixed etiology
Findings
Fatality rate
Of the few studies into the rates and etiology of bacterial meningitis in Malaysia, 10 epidemiological studies were identified for the country, which included 380 cases of bacterial meningitis (TABLES 1 & 2). Few were recent, all studies were hospital based and all but one were retrospective, reviewing patient records and accompanying microbiological results (where available) to draw conclusions regarding the relative meningitis burden by organism and age of patient, among other factors.
These earlier studies showed that not only prevalence but also fatalities due to meningitis were also disproportionately higher in the first year of life; with 10 of the 12 deaths [9] and 9 of 11 deaths [10] occurring in those under a year old. They reveal the first 6 months of life to be particularly vulnerable because they represented roughly two-thirds of deaths in the under 1-year age cohort in both studies. Overall case fatality rates (CFR) from bacterial meningitis in 1 month olds to 12 years was 21 and 19.0% [9,10], respectively. Among a total of
706
Five studies describing 273 cases across the spectrum of bacterial meningitis enabled a comparison of the relative burden of meningitis by etiological agent (TABLE 1) [9–13]. Association with age
The most recent study reviewed patient records for all cases of suspected meningitis admitted to a single center in Kuala Lumpur between 2001 and 2005 [13]. It was the only study of mixed etiology that considered cases across all ages. Of the 47 cases of bacterial meningitis reported in this study, 28 cases occurred in the age group under 10 years old, with 93% afflicting those under 5 years of age. Just 2 cases occurred in the 10to 18-year age group, 12 cases in the 19- to 59-year age range and 3 in patients over 60 years old [13]. The remaining four studies were pediatric focused, also reporting the bulk of cases disproportionately affecting the very young with over 70% among under 12 months olds [9–12]. The proportion of cases in the age group up to 6 months was 53, 64 and 54%, [10–12], and 32% for those under the 2-month age group [9].
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Table 2. Summary of studies of single etiology of meningitis in Malaysia. Ref.
Study period
Focus of study
Location
Age group
% meningitis of total cases of disease (n)
Meningitis case fatality rate (n)
Sep 1971–Jun 1979
Haemophilus influenzae – bacteremia and associated clinical conditions
Single centre, KL†
Neonate 24 months
55% (22)
4.5% (1)
[18]
Jun 1985–Dec 1994
H. influenzae – invasive disease
Single centre, Kelantan‡
1 day–6 years
73.8% (48)
14.6% (7)
[19]
Sep 1981–Aug 1985
Streptococcus pneumoniae – spectrum of infection, prospective study
A major national referral centre§
All ages
21.1 % (19)
No data
[21]
Single centre, KL†
2 weeks to 24 months
11
†
17 of 18 isolates successfully typed were type b. Nenonates specifically excluded from study. All isolates successfully typed were type b.
‡ §
excluded from this study and one fatality was recorded. All the 18 isolates where serotyping was possible were serotype b. S. pneumoniae meningitis burden
Two studies were identified that focused specifically on the burden of pneumococcal disease and included meningitis [21,22]. The pneumococcal meningitis prevalence by age reported in these studies along with that reported in one study of multiple etiologies is shown in TABLE 5. Although the age bands in each of the three studies differed and the number of meningitis cases was very small, it clearly illustrates that the risk of meningococcal meningitis is dramatically higher among the younger age groups, particularly for babies and infants. Between 63 and 79% of S. pneumoniae meningitis cases were reported in the less than 12-month age group. Another study of meningitis of
multiple etiologies also reported pneumococcal meningitis as most prevalent in the 2–12-month age group, with a CFR of 37.5% among eight cases of pneumococcal meningitis [9]. A separate study of meningitis of multiple etiologies reported four deaths from 14 cases attributable to S. pneumoniae [10]. Only four cases of pneumococcal meningitis were identified among 50 isolates in a study reporting on a retrospective study into invasive pneumococcal disease (IPD) of over 5 years [22]. It focused on children under 14 years, an urban hospital serving mainly middle- to lower-income socioeconomic groups. Although the study numbers were very small, it suggests a preponderance of pneumococcal meningitis in the younger age group and a high burden of long-term sequelae. Three of the cases were under 2 years of age (none of whom had underlying health conditions) but all went on to develop serious long-term
Table 4. Organism specific meningitis case fatality rates in Malaysia. Organism
Study (year)
Isolates (n)
Fatalities (n)
Organism specific fatality ratio %
Haemophilus influenzae
Nik Khairulddin et al. (1999)
48
7
14.6
[19]
Choo et al. (1990)
29
4
13.8
[10]
Lyn and Lin (1988)
9
2
22.2
[9]
Puthucheary and Thong (1984)
22
1
4.5
Mean for spp. across studies Streptococcus pneumoniae
Lim et al. (2007)
4
0
0.0
[22]
Choo et al. (1990)
14
4
28.6
[10]
Lyn and Lin (1988)
8
3
37.5
[9]
26.9
Raja et al. (2006)
11
3
27.3
[23]
Choo et al. (1990)
5
0
0.0
[10]
Lyn and Lin (1988)
7
0
0.0
[9]
Mean for spp. across studies Mycobacterium tuberculosis
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[18]
13.0
Mean for spp. across studies Neisseria meningitidis
Ref.
Lyn and Lin (1988)
13.0 8
1
12.5
[9]
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Table 5. Age related prevalence of pneumococcal meningitis in Malaysia.
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Jamal et al. (1987), 38 cases
[21]
Choo et al. (1990), 14 cases†
[10]
Lim et al. (2007), 8 cases
[22]
Age range
% of total study S. pneumoniae cases
Age range
% of total study S. pneumoniae cases
Age range
% of total study S. pneumoniae cases
0 day–3 years
68.4
1–6 months
42.9
5 years
25.0
>12 years
21.1
5–9 years
7.1
10–17 years
7.1
†
Nenonates specifically excluded from study.
sequelae, including cerebral palsy and sensorineural deafness. No mortality data were specifically reported for meningitis. Similarly, a prospective study (n = 90) into the spectrum of IPD disease showed 19 cases of pneumococcal meningitis to be distant second to pneumonia in terms of the overall burden of IPD, over 4 years to 1985 [21]. It included all ages with the meningitis burden greatest in the younger age groups, although no meningitis mortality data were stated. Capsular typing was limited due to laboratory handling errors; however, where it was done, serotypes 4, 6A, 6B, 14 19A and 23 F dominated, all of which are included in the 13-valent pneumococcal conjugate vaccine (PCV13) vaccine. The meningitis CFRs for individual studies, where available, are contrasted in TABLE 4. Although there was a huge range in the CFRs for pneumococcal meningitis, it had the highest mean fatality compared with H. influenzae, N. meningitidis and M. tuberculosis associated meningitis. N. meningitidis burden
A single epidemiological study into N. meningitidis, which included meningococcal meningitis, was identified for Malaysia (TABLE 2) [23]. The study identified patient records for invasive meningococcal disease (IMD), from infancy to old age, for 7 years up to 2004 with 6 of the 13 reported cases of meningococcal meningitis associated with meningococcemia. Among the 10 patients with meningitis where outcome data were available, three deaths were reported TABLE 4. Two survivors exhibited postmeningitis complications, including arthritis and nerves palsies, with further hospitalization required for complications arising from treatment of the primary meningococcal infection. Postulated risk factors included two cases directly linked to a Hajj serogroup W135 outbreak (2000–2001). In one case, the pilgrim had received the polysaccharide ACYW135 conjugate vaccine. Another patient had household contact with a case that died from meningococcal infection (but was not included in this study). Little serogrouping of the etiologic meningococci was performed. Apart from the two Hajj associated cases, a third serogroup W135 meningitis isolate was recorded and one case of serogroup B [23]. In the studies into meningitis of a variety of etiologies [9–13], where the etiology was identified, between 3.5 and 13% of cases were attributed to meningococci. Although any long-term 710
sequelae arising from the meningococcal meningitis in these studies were not detailed, all cases were nonfatal (TABLE 4). Discussion
To the best of the authors’ knowledge, this review includes all available epidemiological studies of vaccine-preventable bacterial meningitis in Malaysia published since 1980 in English. Among the studies into multiple causes of bacterial meningitis, H. influenzae was the most prevalent agent, accounting for over 50% of cases of vaccine-preventable meningitis. In most studies, S. pneumoniae was second to H. influenzae as the greatest cause of meningitis. The one exception was where pneumococcal meningitis outnumbered that of H. influenzae and was the most recent among the studies. This apparent decline in meningitis of H. influenzae compared with that of S. pneumoniae may, in part, reflect a decline in meningitis caused by Hib as a consequence of adding the Hib vaccine to the country’s NIP, which occurred during the period of the study. Where H. influenzae dominated meningitis etiology, the studies predated Hib’s inclusion in Malaysia’s NIP, it reflects findings from both industrialized and developing countries where Hib was the greatest cause of community acquired meningitis, prior to widespread uptake of the Hib vaccine in [24–26]. In all studies of multiple etiology, N. meningitidis and M. tuberculosis were fewer than both H. influenzae and S. pneumoniae in their contribution to overall meningitis burden. Although government statistics stated 100% BCG coverage in 1996 [27], the authors reported that the high proportion of tubercular meningitis occurred among rural and immigrant populations, most of whom had not received BCG immunization at that time [9]. Furthermore, BCG efficacy against meningeal tuberculosis is reported as 69% in Asia [28]. More complete BCG immunization coverage subsequently may account for the drop-off in tubercular meningitis in the later studies of mixed etiology. No studies specifically into M. tuberculosis meningitis incidence or prevalence in Malaysia were found. While the meningitis risk generally declined with increasing age, it should be noted that all but one of the studies to stratify etiology by age were pediatric. The risk of bacterial meningitis to the young is well known; however, a lack of studies into adult meningitis limits our ability to see whether there is a second Expert Rev. Anti Infect. Ther. 13(6), (2015)
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spike in H. influenzae and pneumococcal meningitis among the elderly, as has been reported elsewhere [29]. Two pediatric studies into meningococcal meningitis also reported the greatest number of meningococcal cases among neonates and babies under a year [9,10] although a later study showed a more even distribution of cases across the age range, albeit very small in size [23]. The small case numbers make it impossible to determine whether the greatest spike in meningococcal risk by age in Malaysia is in late adolescence, as with meningococcal meningitis C in other countries, [30], which may be affected by differences in culture and behavior among adolescents and young adults. Comparing organism-specific CFRs between studies showed tremendous variation. In general, CFRs were highest for S. pneumoniae meningitis, followed by H. influenzae. Accurate reporting on long-term morbidity from meningitis was limited by a lack of reporting of the period over which long term sequelae were assessed and due to patients droping out at follow up. Nevertheless, the studies reviewed here substantiate a high risk of debilitating and enduring sequelae resulting from bacterial meningitis, with pneumococcal meningitis considered to carry the highest risk of longterm disabling sequelae [2]. Whether this is also true of Malaysia is impossible to conclude from the low numbers detailed for studies of single etiology. Drawing firm conclusions on the burden of bacterial meningitis in Malaysia is constrained by several limitations. The intervals between studies were long, most were dated and were limited to analysis of pediatric data. Data on meningitis in the adult and elderly populations are particularly scarce, and studies mostly focused on major urban conurbations. Variance in study methodology in terms of case definition and age stratification made comparison between studies difficult. Except for one study, where methodology was not detailed, all the studies reviewed here relied on standard microbiological techniques to identify the etiology. In Asia, the widespread and often indiscriminate use of antibiotics, in advance of a clinical diagnosis of meningitis, may hamper the successful identification of the causative agent, resulting in an underreporting of the disease [31,32]. This is likely a contributory factor to the high proportion of meningitis cases where etiology was unidentified. However, swift treatment of bacterial meningitis is critical to patient outcome, so identification of etiology should not be a reason to delay empirical antibiotic treatment [33]. Several studies also reported on a lack of skills and difficulties in laboratory practice hindering isolation of bacteria, leading to a likely under-reporting of cases. Despite the limitations outlined, it is clear that there is a dearth of quality, long-standing surveillance data from around Malaysia, large enough in scale to be definitive about the true burden of bacterial meningitis and vaccine preventable causes. Such surveillance is not only crucial in making informed decisions on health policy with regards to the cost–effectiveness of adopting existing or newly available vaccines for widespread use [34] but also to assess the effectiveness of vaccine implementation once part of the NIP. In addition, quality surveillance gives crucial early indication of changes in bacterial epidemiology, such as serotype replacement [35,36], and can be used to optimize informahealthcare.com
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immunization schedules following local epidemiological changes, resulting from widespread vaccine implementation [30,37]. Good surveillance can also assist in monitoring changes in antimicrobial resistance, considered a growing problem globally. Resistance is particularly problematic in Asia [38,39], where selective pressure due to injudicious prescribing of antibiotics [16] and poor adherence to dosage regimens is commonplace [40,41]. Meningitic isolates nonsusceptible and resistant to a variety of agents were reported in three studies reviewed [9,10,13], with a far more recent study showing a dramatic rise in penicillin resistance among clinical isolates across the disease spectrum of IPD in Malaysia [42] Furthermore, good quality molecular typing could help elucidate the route and geographical spread of antimicrobial resistant and invasive strains – a need that is particularly addressed by nucleotide sequence-based typing methods [43,44]. Immunization can play a preventative role in the spread of antimicrobial resistance by reducing nasopharyngeal colonization by vaccine serotypes/serogroups, a prerequisite to infection [45] and subsequent need for therapeutic intervention [37]. This effect is magnified when the consequences of herd immunity from a reduction in circulating serotypes are considered [46]. Unfortunately, no complete epidemiological study into Hib meningitis in Malaysia has been done following the vaccine’s inclusion in the NIP and a large-scale epidemiological study of H. influenzae infections to assess its success is overdue. PCVs have been licensed in Malaysia since 2005 but have yet to be included in the NIP although a 2011 study, based on the spectrum of IPD, concluded a favorable cost–effectiveness ratio for routine PCV-7 immunization across the country [47]. Another study estimated inpatient pediatric and adult costs per case of IPD combined with the pediatric and adult outpatient costs to be a total direct cost of RM 3,737,584 for meningitis alone, although whether per hospital or spread across the four centers is not clear [48]. In addition this did not account for the indirect costs, which have been shown to be considerable [49]. Quadrivalent immunization against meningococcal serogroups A, C, W, Y is compulsory for pilgrims attending the Hajj [50], although breakthrough infection or a poor individual response to immunization may occur [23]. Given the tendency of N. meningitidis serogroups to cause outbreaks [51] and the country’s cultural links to the Hajj pilgrimage, meningococcal disease, including meningitis, is a notifiable disease in Malaysia as it is in the Philippines, Singapore and Thailand in South East Asia [32]. This can help contain potential outbreaks by facilitating contact tracing for administration of prophylactic antibiotic treatment to close contacts and disseminate knowledge among local clinicians so they are alert to the risk of a potential outbreak. Expert commentary & five-year view
BCG and Hib immunization will have lead to a decrease in the number of deaths and instances of serious long-term complications resulting from meningitis in Malaysia. However, the absence of large-scale studies before and after their introduction makes it impossible to assess the extent of the success. Even though the Hib vaccine is firmly established in Malaysia’s NIP, 711
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surveillance of meningitis caused by H. influenzae is advisable. The single epidemiological study to include meningitis of H. influenzae since the addition of the Hib vaccine suggests that this organism is still a major cause of meningitis in the country, and appropriate surveillance can assist health authorities to optimize the immunization schedule in response to local epidemiological changes. Among causes of meningitis where widespread immunization is yet to take place, larger, more comprehensive surveillance is required to investigate the need for PCV and meningococcal immunization in Malaysia. This would also be an opportunity to evaluate the success of immunization with follow-up studies should any vaccine be brought into widespread use. In light of the most recent study reviewed here and widespread use of Hib immunization in Malaysia, S. pneumoniae may now be the principle cause of bacterial meningitis. Therefore, it seems probable that a polyvalent PCV will be included in Malaysia’s NIP sooner than any meningococcal vaccine. According to analysis appraising the range of pneumococcal disease, routine immunization of infants with PCV7 would come at a conservative estimated cost–effectiveness ratio of approximately half that of the WHO’s threshold for cost–effectiveness of public health interventions in Malaysia [47]. A similar assessment needs to be done on the cost– effectiveness of PCV10 and PCV13 in Malaysia; however, both vaccines include the majority of serotypes according to an analysis of serotype prevalence of reported clinical pneumococcal serotypes in Malaysia [52]. The Malaysian Ministry of Health is expected to revisit the need for universal infant
immunization with a PCV in 2015. Apparent low numbers of meningococcal meningitis, and other IMD, makes widespread uptake of monovalent and polyvalent meningococcal vaccines highly unlikely at present. How accurate this really is of the epidemiological situation of vaccine preventable meningitis in Malaysia is difficult to say. Improvements in surveillance, laboratory practice and molecular typing are anticipated to greatly improve the understanding of the etiology and antimicrobial resistance epidemiology of vaccine preventable meningitis in Malaysia. Alongside this, immunization presents an opportunity to lessen the disease burden and circumvent the issue of growing antimicrobial resistance. Financial & competing interests disclosure
SC Clarke receives unrestricted research funding from Pfizer Vaccines (previously Wyeth Vaccines) and has participated in advisory boards and expert panels for GSK, Pfizer and Novartis. SC Clarke and JMC Jefferies are investigators on studies conducted on behalf of University Hospital Southampton NHS Foundation Trust/University of Southampton/Public Health England that are sponsored by vaccine manufacturers but receives no personal payments from them. SC Clarke and JMC Jefferies have received financial assistance from vaccine manufacturers to attend conferences. All grants and honoraria are paid into accounts within the respective NHS Trusts or universities, or to independent charities. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Key issues .
The evidence base for vaccine preventable meningitis in Malaysia is inadequate, particularly for adults and elderly populations.
.
Haemophilus influenzae is the single greatest bacterial cause of meningitis in the country; however, no study into its prevalence, compared with other causes of meningitis, has been conducted since inclusion of the H. influenzae type b vaccine into Malaysia’s National Immunisation Programme in 2002.
.
Children under 5 years old are at greatest risk from vaccine preventable meningitis with those under 2 years of age particularly susceptible.
.
According to extremely limited data, Streptococcus pneumoniae has the highest case fatality rate in Malaysia, almost 27%, for meningitis.
.
H. influenzae, Neisseria meningitidis exhibited roughly similar case fatality rates, around 13%, again based on very small-scale studies.
.
Introduction of PCV7 has been adjudged cost–effective on the basis of the expected reduction in the burden of meningitis, notwithstanding the additional cost savings, which could result with the decrease in other invasive pneumococcal diseases. Similar analysis is needed for the more contemporaneous PCV10 and PCV13.
.
All forms of pneumococcal conjugate vaccine would likely protect against the majority of pneumococcal serotypes in circulation in Malaysia.
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Malaysia. Pediatr Infect Dis J 1998; 17(9 Suppl):S189-90
References Papers of special note have been highlighted as: . of interest .. of considerable interest 1.
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
2.
3.
4.
5.
6.
7.
8.
9.
10.
13.
World Health Organisation. Control of epidemic meningococcal disease. WHO practical guidelines Edmond K, Clark A, Korczak VS, et al. Global and regional risk of disabling sequelae from bacterial meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2010;10(5):317-28 Castelblanco RL, Lee M, Hasbun R. Epidemiology of bacterial meningitis in the USA from 1997 to 2010: a population-based observational study. Lancet Infect Dis 2014;14(9):813-19 Satzke C, Turner P, Virolainen-Julkunen A, et al. Standard method for detecting upper respiratory carriage of Streptococcus pneumoniae: updated recommendations from the World Health Organization Pneumococcal Carriage Working Group. Vaccine 2013;32(1):165-79 Franco-Paredes C, Lammoglia L, Herna´ndez I, Santos-Preciado JI. Epidemiology and outcomes of bacterial meningitis in Mexican children: 10-year experience (1993-2003). Int J Infect Dis 2008;12(4):380-6 Robbins JB, Schneerson R, Anderson P, Smith DH. The 1996 Albert Lasker Medical Research Awards. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharide-based vaccines. JAMA 1996;276(14):1181-5 The World Bank Group. Country and Lending Groups. 2014. Available from: http://data.worldbank.org/about/countryand-lending-groups#East_Asia_and_Pacific [20 November 2014] World Health Organization. o.b.o.t.A.P.O. o.H.S.a.P., Malaysia Health System Review; 2013 Lyn P, Pan Fui Lin Management and outcome of childhood meningitis in east Malaysia. Med J Malaysia 1988;43(1):90-6 Choo KE, Ariffin WA, Ahmad T, et al. Pyogenic meningitis in hospitalized children in Kelantan, Malaysia. Ann Trop Paediatr 1990;10(1):89-98
11.
Yeat SW, Mukari SZ, Said H, Motilal R. Post meningitic sensori-neural hearing loss in children – alterations in hearing level. Med J Malaysia 1997;52(3):285-90
12.
Hussain IH, Sofiah A, Ong LC, et al. Haemophilus influenzae meningitis in
informahealthcare.com
Erleena Nur H, Amaiah I, Rohela M, Nissapatorn V. Bacterial meningitis: a five year (2001-2005) retrospective study at university malaya medical center (UMMC), Kuala Lumpur, Malaysia. Southeast Asian J Trop Med Public Health 2008;39:73-7
Special Report
25.
Adegbola RA, Secka O, Lahai G, et al. Elimination of Haemophilus influenzae type b (Hib) disease from The Gambia after the introduction of routine immunisation with a Hib conjugate vaccine: a prospective study. Lancet 2005;366(9480):144-50
26.
Cowgill KD, Ndiritu M, Nyiro J, et al. Effectiveness of Haemophilus influenzae type b Conjugate vaccine introduction into routine childhood immunization in Kenya. JAMA 2006;296(6):671-8
..
The most recent investigation into meningitis of multiple etiology from Malaysia and only one to include all ages.
14.
Lee EI, Khoo BH, Puthucheary SD, Thong ML. Purulent meningitis in childhood. Med J Malaysia 1977;32(2): 114-19
27.
Childhoo Immunisation-Health Technology Assessment, MOH/P/PAK/47.02 (TR). Available from: www.moh.gov.my/ attachments/745.pdf [Cited 2014]
15.
Lolekha S, Cooksley G, Chan V, et al. A review of Hib epidemiology in Asia. Southeast Asian J Trop Med Public Health 2000;31(4):650-7
28.
16.
Peltola H. Spectrum and burden of severe Haemophilus influenzae type b diseases in Asia. Bull World Health Organ 1999; 77(11):878-87
Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet 2006; 367(9517):1173-80
29.
Ciruela P, Martı´nez A, Izquierdo C, et al. Epidemiology of vaccine-preventable invasive diseases in Catalonia in the era of conjugate vaccines. Hum Vaccin Immunother 2013;9(3):681-91
30.
Pollard AJ, Perrett KP, Beverley PC. Maintaining protection against invasive bacteria with protein-polysaccharide conjugate vaccines. Nat Rev Immunol 2009; 9(3):213-20
31.
Halperin SA, Bettinger JA, Greenwood B, et al. The changing and dynamic epidemiology of meningococcal disease. Vaccine 2012;30(Suppl 2):B26-36
32.
Vyse A, Wolter JM, Chen J, et al. Meningococcal disease in Asia: an under-recognized public health burden. Epidemiol Infect 2011;139(7):967-85
.
Reviews the burden of meningococcal meningitis across Asia by serogroups, incidence and case fatality rate.
17.
World Health Organization. Global health indicators. World Health Stat 2012; 2012:Part III
18.
Puthucheary SD, Thong ML. The spectrum of clinical conditions associated with 40 cases of Haemophilus bacteremia. Singapore Med J 1984;25(3):152-6
19.
Nik Khairulddin NY, Choo KE, Johari MR. Epidemiology of Haemophilus influenzae invasive disease in hospitalised Kelantanese children, 1985-1994. Singapore Med J 1999; 40(2):96-100
20.
Likitnukul S. Systemic Haemophilus influenzae disease in Thai children. Southeast Asian J Trop Med Public Health 1994;25(4):672-7
21.
Jamal F, Pit S, Isahak I, et al. Pneumococcal infection in hospitalized patients: a four-year study in Malaysia. Southeast Asian J Trop Med Public Health 1987;18(1):79-84
22.
23.
24.
33.
Lim LH, Lee WS, Parasakthi N. Childhood invasive pneumococcal disease: a hospital-based study from Malaysia. J Paediatr Child Health 2007;43(5):366-9
Proulx N, Frechette D, Toye B, et al. Delays in the administration of antibiotics are associated with mortality from adult acute bacterial meningitis. QJM 2005;98(4): 291-8
34.
Raja NS, Parasakthi N, Puthucheary SD, Kamarulzaman A. Invasive meningococcal disease in the University of Malaya Medical Centre, Kuala Lumpur, Malaysia. J Postgrad Med 2006;52(1):23-9; discussion 29
Richardson A, Morris DE, Clarke SC. Vaccination in Southeast Asia-Reducing meningitis, sepsis and pneumonia with new and existing vaccines. Vaccine 2014;32(33): 4119-23
35.
Alexandre C, Dubos F, Courouble C, et al. Rebound in the incidence of pneumococcal meningitis in northern France: effect of serotype replacement. Acta Paediatr 2010; 99(11):1686-90
36.
Hanage WP, Finkelstein JA, Huang SS, et al. Evidence that pneumococcal serotype
Peltola H. Haemophilus influenzae type b disease and vaccination in Europe: lessons learned. Pediatr Infect Dis J 1998; 17(9 Suppl):S126-32
713
Special Report
McNeil, Jefferies & Clarke
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
replacement in Massachusetts following conjugate vaccination is now complete. Epidemics 2010;2(2):80-4
42.
Le CF, Palanisamy NK, Mohd Yusof MY, Sekaran SD. Capsular serotype and antibiotic resistance of Streptococcus pneumoniae isolates in Malaysia. PLoS One 2011;6(5):e19547
37.
Heath PT, Ramsay ME. Haemophilus influenzae type b vaccine – booster campaign. BMJ 2003;326(7400):1158-9
43.
38.
Song JH, Jung SI, Ko KS, et al. High prevalence of antimicrobial resistance among clinical Streptococcus pneumoniae isolates in Asia (an ANSORP study). Antimicrob Agents Chemother 2004;48(6):2101-7
Jefferies JM, Mohd Yusof MY, Devi Sekaran S, Clarke SC. Novel clones of Streptococcus pneumoniae causing invasive disease in Malaysia. PLoS One 2014;9(6): e97912
44.
39.
Kim SH, Song JH, Chung DR, et al. Changing trends in antimicrobial resistance and serotypes of Streptococcus pneumoniae isolates in Asian countries: an Asian Network for Surveillance of Resistant Pathogens (ANSORP) study. Antimicrob Agents Chemother 2012;56(3):1418-26
Harrison OB, Brueggemann AB, Caugant DA, et al. Molecular typing methods for outbreak detection and surveillance of invasive disease caused by Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae, a review. Microbiology 2011;157(Pt 8): 2181-95
40.
41.
.
Yang YH, Fu SG, Peng H, et al. Abuse of antibiotics in China and its potential interference in determining the etiology of pediatric bacterial diseases. Pediatr Infect Dis J 1993;12(12):986-8
45.
Hung IF, Tantawichien T, Tsai YH, et al. Regional epidemiology of invasive pneumococcal disease in Asian adults: epidemiology, disease burden, serotype distribution, and antimicrobial resistance patterns and prevention. Int J Infect Dis 2013;17(6):e364-73
46.
Recent review of the incidence, mortality and antibiotic resistance associated with invasive pneumococcal disease in Asia.
714
47.
Dagan R. Impact of pneumococcal conjugate vaccine on infections caused by antibiotic-resistant Streptococcus pneumoniae. Clin Microbiol Infect 2009; 15(Suppl 3):16-20 Soriano-Gabarro M, Wolter J, Hogea C, Vyse A. Carriage of Neisseria meningitidis in Europe: a review of studies undertaken in the region. Expert Rev Anti Infect Ther 2011;9(9):761-74 Aljunid S, Abuduxike G, Ahmed Z, et al. Impact of routine PCV7 (Prevenar) vaccination of infants on the clinical and
economic burden of pneumococcal disease in Malaysia. BMC Infect Dis 2011;11:248 .
An investigation into the cost– effectiveness, of implementing widespread PCV7 immunization in Malaysia.
48.
Maimaiti N, Zafar A, Amrizal M, et al. Estimating clinical and economic burden of pneumococcal meningitis in Malaysia using Casemix data. BMC Health Serv Res 2012; 12(Suppl 1):O4
..
A recent summary of the economic costs associated with pediatric and adult pneumococcal meningitis for in-patient and out-patients in Malaysia.
49.
Isaacman DJ, Strutton DR, Kalpas EA, et al. The impact of indirect (herd) protection on the cost-effectiveness of pneumococcal conjugate vaccine. Clin Ther 2008;30(2):341-57
50.
Cohn AC, MacNeil JR, Clark TA, et al. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2013; 62(Rr-2):1-28
51.
Meningococcal disease, serogroup W135. Wkly Epidemiol Rec 2001;76(19):141-2
52.
Jauneikaite E, Jefferies JM, Hibberd ML, Clarke SC. Prevalence of Streptococcus pneumoniae serotypes causing invasive and non-invasive disease in South East Asia: a review. Vaccine 2012;30(24):3503-14
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Vaccine preventable meningitis in Malaysia: epidemiology and management Expert Rev. Anti Infect. Ther. 13(6), 705–714 (2015)
Hannah C McNeil1, Johanna MC Jefferies2 and Stuart C Clarke*1,2 1 University of Southampton Malaysia Campus, No.3, Persiaran Canselor 1, Kota Ilmu, Educity, Iskandar, 79200 Nusajaya, Johor, Malaysia 2 Faculty of Medicine and Institute of Life Sciences, University of Southampton, Southampton, UK *Author for correspondence: Tel.: +60 7560 2469 [email protected]
Worldwide bacterial meningitis accounts for more than one million cases and 135,000 deaths annually. Profound, lasting neurological complications occur in 9–25% of cases. This review confirms the greatest risk from bacterial meningitis is in early life in Malaysia. Much of the disease burden can be avoided by immunization, particularly against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae. Despite inclusion of the Hib vaccine in the National Immunisation Programme and the licensure of pneumococcal vaccines, these two species are the main contributors to bacterial meningitis in Malaysia, with Neisseria meningitidis and Mycobacterium tuberculosis, causing a smaller proportion of disease. The high Hib prevalence may partly be due to dated, small-scale studies limiting the understanding of the current epidemiological situation. This highlights the need for larger, better quality surveillance from Malaysia to evaluate the success of Hib immunization and to help guide immunization policy for vaccines against S. pneumoniae and N. meningitidis. KEYWORDS: etiology . disease surveillance . Haemophilus influenzae . immunization . Malaysia . meningitis .
Mycobacterium tuberculosis
.
Neisseria meningitides . Streptococcus pneumoniae
Bacterial meningitis remains a devastating disease, accounting for at least 1.2 million cases and 135,000 deaths worldwide annually, excluding epidemics [1]. Depending on WHO region, bacterial meningitis leaves 9–25% of survivors with serious and burdensome postdischarge sequelae, including neurological damage, epilepsy, hearing loss, amputation and delayed development. Children under 5 years of age are disproportionately affected [2]. Highly immunogenic conjugate vaccines that induce long-lasting protection are available against the major causes of bacterial meningitis, namely Haemophilus influenzae serotype b (Hib), Streptococcus pneumoniae and Neisseria meningitidis. However, only the Hib vaccine has been added to the National Immunisation Programme (NIP) in Malaysia. There is a wealth of epidemiologic data on the success of immunization programmes in reducing the incidence of meningitis and consequential mortality and morbidity associated with Hib, N. meningitidis and S. pneumoniae, where such vaccination programmes have been informahealthcare.com
10.1586/14787210.2015.1033401
introduced, both in developed and in developing countries [3–6]. Such data for Malaysia are scarcer and sporadic, especially considering its status as an upper middle-income country [7], where health care is heavily subsidized and no one is refused treatment on the basis of an inability to pay [8]. Reviews frequently focus on the burden of meningitis attributable to a single causative organism rather than highlighting the overall disease burden of meningitis. As much of the disease burden of bacterial meningitis is vaccine preventable, this review seeks to collate information in the public domain on potentially avoidable meningitis in Malaysia and obtain a clearer view of burden by etiology. Method
This review seeks to summarize information relevant to the epidemiology and management of vaccine preventable bacterial meningitis for Malaysia, in English language peer-reviewed journals, published since 1980. A literature search was undertaken using PubMed, where
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Table 1. Summary of studies into multiple etiologies of meningitis in Malaysia. Study period
Focus of study
Location
Age group
% cases etiology identified, (n)
Case fatality rate
Ref.
Jan 1983–June 1986
All causes of pediatric meningitis
Single centre, Sabah†
Neonate to 70 years
100% (47)
7/47 (15%)
[13]
[9]
†
Sandakan, Duchess of Kent Hospital. Includes one fungal and 3 viral cases. Hospital Universiti Sains Malaysia, the only tertiary centre serving this rural state for pediatric referrals during study period. ¶ Nenonates specifically excluded from study. # Positive laboratory speciation of agent required for study inclusion. †† TB specifically excluded from study. ‡‡ Pediatric Institute, Kuala Lumpur Hospital. §§ 10 viral cases. ¶¶ Pediatric Institute, Hospital Kuala Lumpur, Kota Bahru Hospital, Kelantan, Hospital Sultanah Aminah, Johor, Hospital Alor Setar, Kedah and Hospital Kuching, Sarawak. ## Number of laboratory confirmed cases of meningitis. ††† Number of cases symptomatic of meningitis. ‡‡‡ University of Malaya Medical Centre. ‡ §
the search for terms was limited to the article title and abstract. Primary search terms included ‘Malaysia’ and ‘bacterial meningitis’. In PubMed the MeSH term ‘bacterial meningitis’ encompasses the following categories; ‘Meningitis, Escherichia coli’, ‘Meningitis, Haemophilus’, ‘Meningitis, Listeria’, ‘Meningitis, Meningococcal’, ‘Meningitis, Pneumococcal’, and ‘Tuberculosis, Meningeal’ and sub-categories thereof. The searches above were repeated with the term, ‘Malaysia’ replaced with ‘Asia’. Additional information came from citations used by articles from the PubMed search. For the purposes of this review, a case of meningitis, or the laboratory definition of meningitis, was accepted as defined by the study’s author(s). Cases of, and studies into, noninfectious, viral, fungal, parasitic meningitis, nontyphoidal salmonellosis, Klebsiella, Staphylococcus aureus, E. coli and Listeria were excluded, except where the findings for these causes of meningitis were inextricably included in the overall findings for studies of multiple etiology. Also excluded were references where the focus was on sampling and diagnostic methods, serotyping methods, nosocomially acquired meningitis, animal meningitis, antimicrobial resistance and drug trials.
Findings: overall meningitis burden of mixed etiology
Findings
Fatality rate
Of the few studies into the rates and etiology of bacterial meningitis in Malaysia, 10 epidemiological studies were identified for the country, which included 380 cases of bacterial meningitis (TABLES 1 & 2). Few were recent, all studies were hospital based and all but one were retrospective, reviewing patient records and accompanying microbiological results (where available) to draw conclusions regarding the relative meningitis burden by organism and age of patient, among other factors.
These earlier studies showed that not only prevalence but also fatalities due to meningitis were also disproportionately higher in the first year of life; with 10 of the 12 deaths [9] and 9 of 11 deaths [10] occurring in those under a year old. They reveal the first 6 months of life to be particularly vulnerable because they represented roughly two-thirds of deaths in the under 1-year age cohort in both studies. Overall case fatality rates (CFR) from bacterial meningitis in 1 month olds to 12 years was 21 and 19.0% [9,10], respectively. Among a total of
706
Five studies describing 273 cases across the spectrum of bacterial meningitis enabled a comparison of the relative burden of meningitis by etiological agent (TABLE 1) [9–13]. Association with age
The most recent study reviewed patient records for all cases of suspected meningitis admitted to a single center in Kuala Lumpur between 2001 and 2005 [13]. It was the only study of mixed etiology that considered cases across all ages. Of the 47 cases of bacterial meningitis reported in this study, 28 cases occurred in the age group under 10 years old, with 93% afflicting those under 5 years of age. Just 2 cases occurred in the 10to 18-year age group, 12 cases in the 19- to 59-year age range and 3 in patients over 60 years old [13]. The remaining four studies were pediatric focused, also reporting the bulk of cases disproportionately affecting the very young with over 70% among under 12 months olds [9–12]. The proportion of cases in the age group up to 6 months was 53, 64 and 54%, [10–12], and 32% for those under the 2-month age group [9].
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Table 2. Summary of studies of single etiology of meningitis in Malaysia. Ref.
Study period
Focus of study
Location
Age group
% meningitis of total cases of disease (n)
Meningitis case fatality rate (n)
Sep 1971–Jun 1979
Haemophilus influenzae – bacteremia and associated clinical conditions
Single centre, KL†
Neonate 24 months
55% (22)
4.5% (1)
[18]
Jun 1985–Dec 1994
H. influenzae – invasive disease
Single centre, Kelantan‡
1 day–6 years
73.8% (48)
14.6% (7)
[19]
Sep 1981–Aug 1985
Streptococcus pneumoniae – spectrum of infection, prospective study
A major national referral centre§
All ages
21.1 % (19)
No data
[21]
Single centre, KL†
2 weeks to 24 months
11
†
17 of 18 isolates successfully typed were type b. Nenonates specifically excluded from study. All isolates successfully typed were type b.
‡ §
excluded from this study and one fatality was recorded. All the 18 isolates where serotyping was possible were serotype b. S. pneumoniae meningitis burden
Two studies were identified that focused specifically on the burden of pneumococcal disease and included meningitis [21,22]. The pneumococcal meningitis prevalence by age reported in these studies along with that reported in one study of multiple etiologies is shown in TABLE 5. Although the age bands in each of the three studies differed and the number of meningitis cases was very small, it clearly illustrates that the risk of meningococcal meningitis is dramatically higher among the younger age groups, particularly for babies and infants. Between 63 and 79% of S. pneumoniae meningitis cases were reported in the less than 12-month age group. Another study of meningitis of
multiple etiologies also reported pneumococcal meningitis as most prevalent in the 2–12-month age group, with a CFR of 37.5% among eight cases of pneumococcal meningitis [9]. A separate study of meningitis of multiple etiologies reported four deaths from 14 cases attributable to S. pneumoniae [10]. Only four cases of pneumococcal meningitis were identified among 50 isolates in a study reporting on a retrospective study into invasive pneumococcal disease (IPD) of over 5 years [22]. It focused on children under 14 years, an urban hospital serving mainly middle- to lower-income socioeconomic groups. Although the study numbers were very small, it suggests a preponderance of pneumococcal meningitis in the younger age group and a high burden of long-term sequelae. Three of the cases were under 2 years of age (none of whom had underlying health conditions) but all went on to develop serious long-term
Table 4. Organism specific meningitis case fatality rates in Malaysia. Organism
Study (year)
Isolates (n)
Fatalities (n)
Organism specific fatality ratio %
Haemophilus influenzae
Nik Khairulddin et al. (1999)
48
7
14.6
[19]
Choo et al. (1990)
29
4
13.8
[10]
Lyn and Lin (1988)
9
2
22.2
[9]
Puthucheary and Thong (1984)
22
1
4.5
Mean for spp. across studies Streptococcus pneumoniae
Lim et al. (2007)
4
0
0.0
[22]
Choo et al. (1990)
14
4
28.6
[10]
Lyn and Lin (1988)
8
3
37.5
[9]
26.9
Raja et al. (2006)
11
3
27.3
[23]
Choo et al. (1990)
5
0
0.0
[10]
Lyn and Lin (1988)
7
0
0.0
[9]
Mean for spp. across studies Mycobacterium tuberculosis
informahealthcare.com
[18]
13.0
Mean for spp. across studies Neisseria meningitidis
Ref.
Lyn and Lin (1988)
13.0 8
1
12.5
[9]
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Table 5. Age related prevalence of pneumococcal meningitis in Malaysia.
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Jamal et al. (1987), 38 cases
[21]
Choo et al. (1990), 14 cases†
[10]
Lim et al. (2007), 8 cases
[22]
Age range
% of total study S. pneumoniae cases
Age range
% of total study S. pneumoniae cases
Age range
% of total study S. pneumoniae cases
0 day–3 years
68.4
1–6 months
42.9
5 years
25.0
>12 years
21.1
5–9 years
7.1
10–17 years
7.1
†
Nenonates specifically excluded from study.
sequelae, including cerebral palsy and sensorineural deafness. No mortality data were specifically reported for meningitis. Similarly, a prospective study (n = 90) into the spectrum of IPD disease showed 19 cases of pneumococcal meningitis to be distant second to pneumonia in terms of the overall burden of IPD, over 4 years to 1985 [21]. It included all ages with the meningitis burden greatest in the younger age groups, although no meningitis mortality data were stated. Capsular typing was limited due to laboratory handling errors; however, where it was done, serotypes 4, 6A, 6B, 14 19A and 23 F dominated, all of which are included in the 13-valent pneumococcal conjugate vaccine (PCV13) vaccine. The meningitis CFRs for individual studies, where available, are contrasted in TABLE 4. Although there was a huge range in the CFRs for pneumococcal meningitis, it had the highest mean fatality compared with H. influenzae, N. meningitidis and M. tuberculosis associated meningitis. N. meningitidis burden
A single epidemiological study into N. meningitidis, which included meningococcal meningitis, was identified for Malaysia (TABLE 2) [23]. The study identified patient records for invasive meningococcal disease (IMD), from infancy to old age, for 7 years up to 2004 with 6 of the 13 reported cases of meningococcal meningitis associated with meningococcemia. Among the 10 patients with meningitis where outcome data were available, three deaths were reported TABLE 4. Two survivors exhibited postmeningitis complications, including arthritis and nerves palsies, with further hospitalization required for complications arising from treatment of the primary meningococcal infection. Postulated risk factors included two cases directly linked to a Hajj serogroup W135 outbreak (2000–2001). In one case, the pilgrim had received the polysaccharide ACYW135 conjugate vaccine. Another patient had household contact with a case that died from meningococcal infection (but was not included in this study). Little serogrouping of the etiologic meningococci was performed. Apart from the two Hajj associated cases, a third serogroup W135 meningitis isolate was recorded and one case of serogroup B [23]. In the studies into meningitis of a variety of etiologies [9–13], where the etiology was identified, between 3.5 and 13% of cases were attributed to meningococci. Although any long-term 710
sequelae arising from the meningococcal meningitis in these studies were not detailed, all cases were nonfatal (TABLE 4). Discussion
To the best of the authors’ knowledge, this review includes all available epidemiological studies of vaccine-preventable bacterial meningitis in Malaysia published since 1980 in English. Among the studies into multiple causes of bacterial meningitis, H. influenzae was the most prevalent agent, accounting for over 50% of cases of vaccine-preventable meningitis. In most studies, S. pneumoniae was second to H. influenzae as the greatest cause of meningitis. The one exception was where pneumococcal meningitis outnumbered that of H. influenzae and was the most recent among the studies. This apparent decline in meningitis of H. influenzae compared with that of S. pneumoniae may, in part, reflect a decline in meningitis caused by Hib as a consequence of adding the Hib vaccine to the country’s NIP, which occurred during the period of the study. Where H. influenzae dominated meningitis etiology, the studies predated Hib’s inclusion in Malaysia’s NIP, it reflects findings from both industrialized and developing countries where Hib was the greatest cause of community acquired meningitis, prior to widespread uptake of the Hib vaccine in [24–26]. In all studies of multiple etiology, N. meningitidis and M. tuberculosis were fewer than both H. influenzae and S. pneumoniae in their contribution to overall meningitis burden. Although government statistics stated 100% BCG coverage in 1996 [27], the authors reported that the high proportion of tubercular meningitis occurred among rural and immigrant populations, most of whom had not received BCG immunization at that time [9]. Furthermore, BCG efficacy against meningeal tuberculosis is reported as 69% in Asia [28]. More complete BCG immunization coverage subsequently may account for the drop-off in tubercular meningitis in the later studies of mixed etiology. No studies specifically into M. tuberculosis meningitis incidence or prevalence in Malaysia were found. While the meningitis risk generally declined with increasing age, it should be noted that all but one of the studies to stratify etiology by age were pediatric. The risk of bacterial meningitis to the young is well known; however, a lack of studies into adult meningitis limits our ability to see whether there is a second Expert Rev. Anti Infect. Ther. 13(6), (2015)
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Vaccine preventable meningitis in Malaysia
spike in H. influenzae and pneumococcal meningitis among the elderly, as has been reported elsewhere [29]. Two pediatric studies into meningococcal meningitis also reported the greatest number of meningococcal cases among neonates and babies under a year [9,10] although a later study showed a more even distribution of cases across the age range, albeit very small in size [23]. The small case numbers make it impossible to determine whether the greatest spike in meningococcal risk by age in Malaysia is in late adolescence, as with meningococcal meningitis C in other countries, [30], which may be affected by differences in culture and behavior among adolescents and young adults. Comparing organism-specific CFRs between studies showed tremendous variation. In general, CFRs were highest for S. pneumoniae meningitis, followed by H. influenzae. Accurate reporting on long-term morbidity from meningitis was limited by a lack of reporting of the period over which long term sequelae were assessed and due to patients droping out at follow up. Nevertheless, the studies reviewed here substantiate a high risk of debilitating and enduring sequelae resulting from bacterial meningitis, with pneumococcal meningitis considered to carry the highest risk of longterm disabling sequelae [2]. Whether this is also true of Malaysia is impossible to conclude from the low numbers detailed for studies of single etiology. Drawing firm conclusions on the burden of bacterial meningitis in Malaysia is constrained by several limitations. The intervals between studies were long, most were dated and were limited to analysis of pediatric data. Data on meningitis in the adult and elderly populations are particularly scarce, and studies mostly focused on major urban conurbations. Variance in study methodology in terms of case definition and age stratification made comparison between studies difficult. Except for one study, where methodology was not detailed, all the studies reviewed here relied on standard microbiological techniques to identify the etiology. In Asia, the widespread and often indiscriminate use of antibiotics, in advance of a clinical diagnosis of meningitis, may hamper the successful identification of the causative agent, resulting in an underreporting of the disease [31,32]. This is likely a contributory factor to the high proportion of meningitis cases where etiology was unidentified. However, swift treatment of bacterial meningitis is critical to patient outcome, so identification of etiology should not be a reason to delay empirical antibiotic treatment [33]. Several studies also reported on a lack of skills and difficulties in laboratory practice hindering isolation of bacteria, leading to a likely under-reporting of cases. Despite the limitations outlined, it is clear that there is a dearth of quality, long-standing surveillance data from around Malaysia, large enough in scale to be definitive about the true burden of bacterial meningitis and vaccine preventable causes. Such surveillance is not only crucial in making informed decisions on health policy with regards to the cost–effectiveness of adopting existing or newly available vaccines for widespread use [34] but also to assess the effectiveness of vaccine implementation once part of the NIP. In addition, quality surveillance gives crucial early indication of changes in bacterial epidemiology, such as serotype replacement [35,36], and can be used to optimize informahealthcare.com
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immunization schedules following local epidemiological changes, resulting from widespread vaccine implementation [30,37]. Good surveillance can also assist in monitoring changes in antimicrobial resistance, considered a growing problem globally. Resistance is particularly problematic in Asia [38,39], where selective pressure due to injudicious prescribing of antibiotics [16] and poor adherence to dosage regimens is commonplace [40,41]. Meningitic isolates nonsusceptible and resistant to a variety of agents were reported in three studies reviewed [9,10,13], with a far more recent study showing a dramatic rise in penicillin resistance among clinical isolates across the disease spectrum of IPD in Malaysia [42] Furthermore, good quality molecular typing could help elucidate the route and geographical spread of antimicrobial resistant and invasive strains – a need that is particularly addressed by nucleotide sequence-based typing methods [43,44]. Immunization can play a preventative role in the spread of antimicrobial resistance by reducing nasopharyngeal colonization by vaccine serotypes/serogroups, a prerequisite to infection [45] and subsequent need for therapeutic intervention [37]. This effect is magnified when the consequences of herd immunity from a reduction in circulating serotypes are considered [46]. Unfortunately, no complete epidemiological study into Hib meningitis in Malaysia has been done following the vaccine’s inclusion in the NIP and a large-scale epidemiological study of H. influenzae infections to assess its success is overdue. PCVs have been licensed in Malaysia since 2005 but have yet to be included in the NIP although a 2011 study, based on the spectrum of IPD, concluded a favorable cost–effectiveness ratio for routine PCV-7 immunization across the country [47]. Another study estimated inpatient pediatric and adult costs per case of IPD combined with the pediatric and adult outpatient costs to be a total direct cost of RM 3,737,584 for meningitis alone, although whether per hospital or spread across the four centers is not clear [48]. In addition this did not account for the indirect costs, which have been shown to be considerable [49]. Quadrivalent immunization against meningococcal serogroups A, C, W, Y is compulsory for pilgrims attending the Hajj [50], although breakthrough infection or a poor individual response to immunization may occur [23]. Given the tendency of N. meningitidis serogroups to cause outbreaks [51] and the country’s cultural links to the Hajj pilgrimage, meningococcal disease, including meningitis, is a notifiable disease in Malaysia as it is in the Philippines, Singapore and Thailand in South East Asia [32]. This can help contain potential outbreaks by facilitating contact tracing for administration of prophylactic antibiotic treatment to close contacts and disseminate knowledge among local clinicians so they are alert to the risk of a potential outbreak. Expert commentary & five-year view
BCG and Hib immunization will have lead to a decrease in the number of deaths and instances of serious long-term complications resulting from meningitis in Malaysia. However, the absence of large-scale studies before and after their introduction makes it impossible to assess the extent of the success. Even though the Hib vaccine is firmly established in Malaysia’s NIP, 711
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surveillance of meningitis caused by H. influenzae is advisable. The single epidemiological study to include meningitis of H. influenzae since the addition of the Hib vaccine suggests that this organism is still a major cause of meningitis in the country, and appropriate surveillance can assist health authorities to optimize the immunization schedule in response to local epidemiological changes. Among causes of meningitis where widespread immunization is yet to take place, larger, more comprehensive surveillance is required to investigate the need for PCV and meningococcal immunization in Malaysia. This would also be an opportunity to evaluate the success of immunization with follow-up studies should any vaccine be brought into widespread use. In light of the most recent study reviewed here and widespread use of Hib immunization in Malaysia, S. pneumoniae may now be the principle cause of bacterial meningitis. Therefore, it seems probable that a polyvalent PCV will be included in Malaysia’s NIP sooner than any meningococcal vaccine. According to analysis appraising the range of pneumococcal disease, routine immunization of infants with PCV7 would come at a conservative estimated cost–effectiveness ratio of approximately half that of the WHO’s threshold for cost–effectiveness of public health interventions in Malaysia [47]. A similar assessment needs to be done on the cost– effectiveness of PCV10 and PCV13 in Malaysia; however, both vaccines include the majority of serotypes according to an analysis of serotype prevalence of reported clinical pneumococcal serotypes in Malaysia [52]. The Malaysian Ministry of Health is expected to revisit the need for universal infant
immunization with a PCV in 2015. Apparent low numbers of meningococcal meningitis, and other IMD, makes widespread uptake of monovalent and polyvalent meningococcal vaccines highly unlikely at present. How accurate this really is of the epidemiological situation of vaccine preventable meningitis in Malaysia is difficult to say. Improvements in surveillance, laboratory practice and molecular typing are anticipated to greatly improve the understanding of the etiology and antimicrobial resistance epidemiology of vaccine preventable meningitis in Malaysia. Alongside this, immunization presents an opportunity to lessen the disease burden and circumvent the issue of growing antimicrobial resistance. Financial & competing interests disclosure
SC Clarke receives unrestricted research funding from Pfizer Vaccines (previously Wyeth Vaccines) and has participated in advisory boards and expert panels for GSK, Pfizer and Novartis. SC Clarke and JMC Jefferies are investigators on studies conducted on behalf of University Hospital Southampton NHS Foundation Trust/University of Southampton/Public Health England that are sponsored by vaccine manufacturers but receives no personal payments from them. SC Clarke and JMC Jefferies have received financial assistance from vaccine manufacturers to attend conferences. All grants and honoraria are paid into accounts within the respective NHS Trusts or universities, or to independent charities. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Key issues .
The evidence base for vaccine preventable meningitis in Malaysia is inadequate, particularly for adults and elderly populations.
.
Haemophilus influenzae is the single greatest bacterial cause of meningitis in the country; however, no study into its prevalence, compared with other causes of meningitis, has been conducted since inclusion of the H. influenzae type b vaccine into Malaysia’s National Immunisation Programme in 2002.
.
Children under 5 years old are at greatest risk from vaccine preventable meningitis with those under 2 years of age particularly susceptible.
.
According to extremely limited data, Streptococcus pneumoniae has the highest case fatality rate in Malaysia, almost 27%, for meningitis.
.
H. influenzae, Neisseria meningitidis exhibited roughly similar case fatality rates, around 13%, again based on very small-scale studies.
.
Introduction of PCV7 has been adjudged cost–effective on the basis of the expected reduction in the burden of meningitis, notwithstanding the additional cost savings, which could result with the decrease in other invasive pneumococcal diseases. Similar analysis is needed for the more contemporaneous PCV10 and PCV13.
.
All forms of pneumococcal conjugate vaccine would likely protect against the majority of pneumococcal serotypes in circulation in Malaysia.
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Vaccine preventable meningitis in Malaysia
Malaysia. Pediatr Infect Dis J 1998; 17(9 Suppl):S189-90
References Papers of special note have been highlighted as: . of interest .. of considerable interest 1.
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
2.
3.
4.
5.
6.
7.
8.
9.
10.
13.
World Health Organisation. Control of epidemic meningococcal disease. WHO practical guidelines Edmond K, Clark A, Korczak VS, et al. Global and regional risk of disabling sequelae from bacterial meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2010;10(5):317-28 Castelblanco RL, Lee M, Hasbun R. Epidemiology of bacterial meningitis in the USA from 1997 to 2010: a population-based observational study. Lancet Infect Dis 2014;14(9):813-19 Satzke C, Turner P, Virolainen-Julkunen A, et al. Standard method for detecting upper respiratory carriage of Streptococcus pneumoniae: updated recommendations from the World Health Organization Pneumococcal Carriage Working Group. Vaccine 2013;32(1):165-79 Franco-Paredes C, Lammoglia L, Herna´ndez I, Santos-Preciado JI. Epidemiology and outcomes of bacterial meningitis in Mexican children: 10-year experience (1993-2003). Int J Infect Dis 2008;12(4):380-6 Robbins JB, Schneerson R, Anderson P, Smith DH. The 1996 Albert Lasker Medical Research Awards. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharide-based vaccines. JAMA 1996;276(14):1181-5 The World Bank Group. Country and Lending Groups. 2014. Available from: http://data.worldbank.org/about/countryand-lending-groups#East_Asia_and_Pacific [20 November 2014] World Health Organization. o.b.o.t.A.P.O. o.H.S.a.P., Malaysia Health System Review; 2013 Lyn P, Pan Fui Lin Management and outcome of childhood meningitis in east Malaysia. Med J Malaysia 1988;43(1):90-6 Choo KE, Ariffin WA, Ahmad T, et al. Pyogenic meningitis in hospitalized children in Kelantan, Malaysia. Ann Trop Paediatr 1990;10(1):89-98
11.
Yeat SW, Mukari SZ, Said H, Motilal R. Post meningitic sensori-neural hearing loss in children – alterations in hearing level. Med J Malaysia 1997;52(3):285-90
12.
Hussain IH, Sofiah A, Ong LC, et al. Haemophilus influenzae meningitis in
informahealthcare.com
Erleena Nur H, Amaiah I, Rohela M, Nissapatorn V. Bacterial meningitis: a five year (2001-2005) retrospective study at university malaya medical center (UMMC), Kuala Lumpur, Malaysia. Southeast Asian J Trop Med Public Health 2008;39:73-7
Special Report
25.
Adegbola RA, Secka O, Lahai G, et al. Elimination of Haemophilus influenzae type b (Hib) disease from The Gambia after the introduction of routine immunisation with a Hib conjugate vaccine: a prospective study. Lancet 2005;366(9480):144-50
26.
Cowgill KD, Ndiritu M, Nyiro J, et al. Effectiveness of Haemophilus influenzae type b Conjugate vaccine introduction into routine childhood immunization in Kenya. JAMA 2006;296(6):671-8
..
The most recent investigation into meningitis of multiple etiology from Malaysia and only one to include all ages.
14.
Lee EI, Khoo BH, Puthucheary SD, Thong ML. Purulent meningitis in childhood. Med J Malaysia 1977;32(2): 114-19
27.
Childhoo Immunisation-Health Technology Assessment, MOH/P/PAK/47.02 (TR). Available from: www.moh.gov.my/ attachments/745.pdf [Cited 2014]
15.
Lolekha S, Cooksley G, Chan V, et al. A review of Hib epidemiology in Asia. Southeast Asian J Trop Med Public Health 2000;31(4):650-7
28.
16.
Peltola H. Spectrum and burden of severe Haemophilus influenzae type b diseases in Asia. Bull World Health Organ 1999; 77(11):878-87
Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet 2006; 367(9517):1173-80
29.
Ciruela P, Martı´nez A, Izquierdo C, et al. Epidemiology of vaccine-preventable invasive diseases in Catalonia in the era of conjugate vaccines. Hum Vaccin Immunother 2013;9(3):681-91
30.
Pollard AJ, Perrett KP, Beverley PC. Maintaining protection against invasive bacteria with protein-polysaccharide conjugate vaccines. Nat Rev Immunol 2009; 9(3):213-20
31.
Halperin SA, Bettinger JA, Greenwood B, et al. The changing and dynamic epidemiology of meningococcal disease. Vaccine 2012;30(Suppl 2):B26-36
32.
Vyse A, Wolter JM, Chen J, et al. Meningococcal disease in Asia: an under-recognized public health burden. Epidemiol Infect 2011;139(7):967-85
.
Reviews the burden of meningococcal meningitis across Asia by serogroups, incidence and case fatality rate.
17.
World Health Organization. Global health indicators. World Health Stat 2012; 2012:Part III
18.
Puthucheary SD, Thong ML. The spectrum of clinical conditions associated with 40 cases of Haemophilus bacteremia. Singapore Med J 1984;25(3):152-6
19.
Nik Khairulddin NY, Choo KE, Johari MR. Epidemiology of Haemophilus influenzae invasive disease in hospitalised Kelantanese children, 1985-1994. Singapore Med J 1999; 40(2):96-100
20.
Likitnukul S. Systemic Haemophilus influenzae disease in Thai children. Southeast Asian J Trop Med Public Health 1994;25(4):672-7
21.
Jamal F, Pit S, Isahak I, et al. Pneumococcal infection in hospitalized patients: a four-year study in Malaysia. Southeast Asian J Trop Med Public Health 1987;18(1):79-84
22.
23.
24.
33.
Lim LH, Lee WS, Parasakthi N. Childhood invasive pneumococcal disease: a hospital-based study from Malaysia. J Paediatr Child Health 2007;43(5):366-9
Proulx N, Frechette D, Toye B, et al. Delays in the administration of antibiotics are associated with mortality from adult acute bacterial meningitis. QJM 2005;98(4): 291-8
34.
Raja NS, Parasakthi N, Puthucheary SD, Kamarulzaman A. Invasive meningococcal disease in the University of Malaya Medical Centre, Kuala Lumpur, Malaysia. J Postgrad Med 2006;52(1):23-9; discussion 29
Richardson A, Morris DE, Clarke SC. Vaccination in Southeast Asia-Reducing meningitis, sepsis and pneumonia with new and existing vaccines. Vaccine 2014;32(33): 4119-23
35.
Alexandre C, Dubos F, Courouble C, et al. Rebound in the incidence of pneumococcal meningitis in northern France: effect of serotype replacement. Acta Paediatr 2010; 99(11):1686-90
36.
Hanage WP, Finkelstein JA, Huang SS, et al. Evidence that pneumococcal serotype
Peltola H. Haemophilus influenzae type b disease and vaccination in Europe: lessons learned. Pediatr Infect Dis J 1998; 17(9 Suppl):S126-32
713
Special Report
McNeil, Jefferies & Clarke
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
replacement in Massachusetts following conjugate vaccination is now complete. Epidemics 2010;2(2):80-4
42.
Le CF, Palanisamy NK, Mohd Yusof MY, Sekaran SD. Capsular serotype and antibiotic resistance of Streptococcus pneumoniae isolates in Malaysia. PLoS One 2011;6(5):e19547
37.
Heath PT, Ramsay ME. Haemophilus influenzae type b vaccine – booster campaign. BMJ 2003;326(7400):1158-9
43.
38.
Song JH, Jung SI, Ko KS, et al. High prevalence of antimicrobial resistance among clinical Streptococcus pneumoniae isolates in Asia (an ANSORP study). Antimicrob Agents Chemother 2004;48(6):2101-7
Jefferies JM, Mohd Yusof MY, Devi Sekaran S, Clarke SC. Novel clones of Streptococcus pneumoniae causing invasive disease in Malaysia. PLoS One 2014;9(6): e97912
44.
39.
Kim SH, Song JH, Chung DR, et al. Changing trends in antimicrobial resistance and serotypes of Streptococcus pneumoniae isolates in Asian countries: an Asian Network for Surveillance of Resistant Pathogens (ANSORP) study. Antimicrob Agents Chemother 2012;56(3):1418-26
Harrison OB, Brueggemann AB, Caugant DA, et al. Molecular typing methods for outbreak detection and surveillance of invasive disease caused by Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae, a review. Microbiology 2011;157(Pt 8): 2181-95
40.
41.
.
Yang YH, Fu SG, Peng H, et al. Abuse of antibiotics in China and its potential interference in determining the etiology of pediatric bacterial diseases. Pediatr Infect Dis J 1993;12(12):986-8
45.
Hung IF, Tantawichien T, Tsai YH, et al. Regional epidemiology of invasive pneumococcal disease in Asian adults: epidemiology, disease burden, serotype distribution, and antimicrobial resistance patterns and prevention. Int J Infect Dis 2013;17(6):e364-73
46.
Recent review of the incidence, mortality and antibiotic resistance associated with invasive pneumococcal disease in Asia.
714
47.
Dagan R. Impact of pneumococcal conjugate vaccine on infections caused by antibiotic-resistant Streptococcus pneumoniae. Clin Microbiol Infect 2009; 15(Suppl 3):16-20 Soriano-Gabarro M, Wolter J, Hogea C, Vyse A. Carriage of Neisseria meningitidis in Europe: a review of studies undertaken in the region. Expert Rev Anti Infect Ther 2011;9(9):761-74 Aljunid S, Abuduxike G, Ahmed Z, et al. Impact of routine PCV7 (Prevenar) vaccination of infants on the clinical and
economic burden of pneumococcal disease in Malaysia. BMC Infect Dis 2011;11:248 .
An investigation into the cost– effectiveness, of implementing widespread PCV7 immunization in Malaysia.
48.
Maimaiti N, Zafar A, Amrizal M, et al. Estimating clinical and economic burden of pneumococcal meningitis in Malaysia using Casemix data. BMC Health Serv Res 2012; 12(Suppl 1):O4
..
A recent summary of the economic costs associated with pediatric and adult pneumococcal meningitis for in-patient and out-patients in Malaysia.
49.
Isaacman DJ, Strutton DR, Kalpas EA, et al. The impact of indirect (herd) protection on the cost-effectiveness of pneumococcal conjugate vaccine. Clin Ther 2008;30(2):341-57
50.
Cohn AC, MacNeil JR, Clark TA, et al. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2013; 62(Rr-2):1-28
51.
Meningococcal disease, serogroup W135. Wkly Epidemiol Rec 2001;76(19):141-2
52.
Jauneikaite E, Jefferies JM, Hibberd ML, Clarke SC. Prevalence of Streptococcus pneumoniae serotypes causing invasive and non-invasive disease in South East Asia: a review. Vaccine 2012;30(24):3503-14
Expert Rev. Anti Infect. Ther. 13(6), (2015)
