Report on the outbreak of Meningococcal diseases in Myanmar 1992-2004, with reference to clinico-epidemiological features, laboratory diagnosis and outbreak management

Introduction

Meningococcal meningitis occurred in Myanmar sporadically and outbreaks were infrequent until 1992 when an outbreak occurred in Pyawbwe town in Mandalaydivision(1)(Ye Myint, et.Al., 1992)In the same year, outbreaks occurred in Kalaymyo in SagaingDivision, Hteelin in Magway Division and Mongpan in Shan State. Since then meningococcal diseases remained endemic and outbreaks occurred in plain areas in Mandalay, Sagaing,Magway Division and NorthernRakhineState and KayahState and Shan plateau. Meningococcal disease mainly occurred in Central Myanmar areas, Mandalay, Magway and Lower SagaingDivisions where the climate was hot, dry and dusty. In recent years most cases or the cause of the outbreak was confirmed by CSF culture and latex agglutination test or cases could be classified as probable by finding Gram negative intracellular diplococci(2).( SoeSoe Aye et al ,2001) The outbreaks were contained by enhanced surveillance, early detection and effective case management. During past fewyears meningococcal diseases were detected as sporadic cases and outbreaks are infrequent.Only sporadic cases occurred in Yangon, Mandalay, and Shan state in 2001, Mandalay in 2002 and Ayeyarwaddyand Magway Divisions in 2003.(SoeLwinNyein, et.al.)

Surveillance

Data on clinical,epidemiological features and laboratory results were collected during outbreak investigation which was carried out by a team of epidemiologists, microbiologists, health directors and team leaders of Special Diseases Control Units located at State or Divisional Health Department concerned. Physicians became part of the team, especially in large outbreaks to manage the cases of meningococcal diseases in recent years. The use of standard case definition(WHO guidelines, Lyon, Foundation Merieux, 1995,(3) Ye Hla,Department of Health, 1999)(4)waspromoted in 1997 and cases were defined as meningococcal diseases covering meningitis ormeningococcaemia and combination of both conditions.

Case definition

Meningococcal diseases (Meningitis and Meningococcaemia)

Suspected

• Sudden onset of fever (>38.5° C rectal, 38.0°C axilla)and one of the following
• Stiff neck
• Altered consciousness
• Other meningeal signs (severe headache, vomiting and/or petechial or purpuric rash

Probable

• Suspected case as defined above and
• Turbid CSF with or without Gram stain positive or
• Ongoing epidemic and epidemiological link to a confirmed case

Confirmed

• Suspected or probable case with positive CSF antigen detection or Positive CSF antigen detection or positive culture of CSF or blood

Laboratory diagnosis

Lumber puncture was done for every admitted case for the examination of cerebrospinal fluid suspected of meningitis and meningococcaemia. Cerebrospinal fluid was examined for turbidity, Gram staining and latex agglutination test(WHO guidelines, Lyon, Foundation Merieux, 1995).(3)Culture was done for some cases in the early phase of outbreak. Specimens were sent in sterile bottle at ambient temperature. Although some contamination was unavoidable in long journey in six hours, isolation could still be done. For latex agglutination test,Slidex Meningitis Kit-5 (BioMerieux, France) was used, which can identify H.influenzae type B, N.menigitidis A, B, C or Streptococcus pneumoniae. Test kit for univalent Meningitis type A was sometimes used. The test was done at township hospital and cerebrospinal fluid was centrifuged in hand-operated centrifuge and warmed in hot water in a kitchen pot just like a water bath in the laboratory. Methylene blue stain was rarely used. Cell counts and biochemical analysis for sugar or protein was seldom done. Sensitivity was done for isolates.

Results

Outbreaks in 1999

Epidemiology

The outbreak in ThabeikkyinTownship started from a small village where many people from different part of the country conglomeratedfor local exploration of gold. Spread occurred to adjacent township, Moemeik in Shan State North and reached epidemic proportion almost at the same period.The daily and weekly data of outbreak was analyzed.Successive waves of cases was seen as spread to villages occurred by population movement and from the epicenter of the outbreak the disease spread to contiguous villages and finally to the town centre.

Figure (1) Cases and deaths of meningococcal diseases by week of onset,ThabeikkyinTownship, Mandalay Division, February to May 1999

The outbreak lasted for about 12 weeks (Figure 1) and sporadic and widely scattered cases were detected by continued surveillance. Attack rate by age group showed all age groups were attacked and was markedly high in 5 to 9 years age group.The male to female sex ratio was 1.45 to 1. The village or ward-wise attack rate ranged from 16 to 1933 per 100,000 populations. The attack rate for the whole township was 93.4 per 100,000 population. Case fatality ratio was 16.7 per cent if early cases not admitted to hospital were included.

Figure (2) Cases and deaths of meningococcal diseases by week of onset,MoemeikTownship, Shan State North, February to May 1999

Other major outbreaks occurred in Moemeik Township almost at the same period, and first case had onset of symptoms on 14 February. Outbreak also lasted for 12 weeks followed by few sporadic cases. Figure (2) Age specific attack rate showed that all age groups were attacked but was much higher in younger age groups. The highest rate was seen in 5 to 9 years age group in both Thabeikkyin and Moemeik townships. (Figure 3)The proportion of cases under five was 26.3 per cent. Cases under 15 years of age constituted 46.7 per cent. Ward or village-wise attack rates ranged from 106.3 to 3056 per 100,000 populations. (Moe Swe, Department of Health, 2000)Township attack rate was 235.33 per 100,000 populations(5). Sex ratio was 1.17 to 1. Case fatality ratio was 10.53 per cent. Malaria parasites were detected in 66 (43 %) of cases. Five cases from adjoining local regiment and family line became ill with meningitis.The climate during that particular period of about four months wasfavourable for disease transmission. Outbreaks remained unabated throughout the hot, dry season and ended with the onset of rain. Similar climatic condition prevailed during the very first outbreak in Pwebwe(YeMyint et al 1992) in 1992.

Figure (3) Age specific attack rate of Meningococcal diseases in Moemeikand Thabeikkyin townships, 1999

During the same season of the year small outbreaks occurred in adjacent townships; Kantbalu from Sagaing Division, Mabein adjoiningMoemeik and Naungcho townships.Sporadic cases were detected in Amarupura, Myitthar, and Moegoke. Isolated case from Amarapura was culture-positive.One case suffered from right-sided hemiplegia and died. One isolated case from Myitthar had a combination of meningitis and meningococcaemia with coma and shock. One rifleman from Mandalay was affected and became afatality. One case was reported from downtown Yangon.

Clinical features

The presentation of clinical signs and symptoms were totaled for the two townships and presented. The fever, vomiting, headache and neck rigidity were most common symptoms and typical haemorrhagic rash was found in 17 per cent of cases. (Figure 4) The clinical types of meningococcal diseases found in 1999 outbreaks were meningitis (82%), meningococcaemia (4%), and combination of both conditions (14%).

Figure (4) Proportion of symptoms and signs of Meningococcal diseases in outbreaks in 1999.

Laboratory diagnosis

Cerebrospinal fluid was found to be grey white in colour or lychee-juice coloured or occasionally clear. Even thick pus exuded from the spinal tap for some cases from Moemeik. Gram negative intracellular diplococci were detected in most cases examined, 67.7 per cent of Moemeik cases and 54 per cent of Thabeikkyin cases. The laboratory results of tests done in four townships were shown in Table 1. The appearance of cerebrospinal fluid by test results was shown in Table 2. Organisms could be seen in samples of CSF even in clear fluid and Gram staining of CSF showed positive results. Confirmation by culture and isolation of organisms was made in few early cases as far as resources permitted. Confirmation could be done by latex agglutination tests and positive in 80 per cent of cases tested. Three casesfrom Moegoke had CSF examined. CSF was turbid, Gram negative diplococci were found in two cases, latex antigen was positive in one case. Cell counts and test for protein and sugar was done. Sugar was absent, protein was increased over 100mg % and cell count was increased. One case was picked up by the epidemiologist himself and proved by CSF examination as a case of meningococcal meningitis. CSF had cell count of 2835 per cubic mm and the majority was polymorph. Oneexperienced technicianin that township hospitaldemonstrated the presence of intracellular diplococci by staining with methylene blue stain.

Table 1. Laboratory results of meningococcal diseases cases in 1999

Table 2.CSF appearance by test result in1999

Outbreaks in 2000

Epidemiology

Outbreaks for that year started in a small village in MyaingTownship in Magway Division, Central dry zone of Myanmar in January. Out of 23 cases, three were fatal. They died of combined meningitis and meningococcaemia. Severe extensive blotchy ecch ymotic rashes were seen(Figure.5). Almost at the same period in January, outbreaks occurred in WindwinTownship and number of reported cases was 35 with six fatalities. Outbreaks occurred widespread and Mandalay city was attacked. Then the number of outbreaks, defined as more than three cases,reported for the whole year, totaled up to 14 and sporadic cases had occurred in 23 townships. Surveillance system was able to detect a few (1 to 3 cases) sporadic cases in each township. Six cases from Bago, 50 miles north of Yangon, were monks from a big monastery.Outbreaks occurred mainly in Mandalay city and Division, and Magway Division. Sporadic cases were reported in Bago, Sagaing, Yangon Divisions, Kachin and ShanState. The casefatality rate for Mandalay Division was 7.3% due to early diagnosis by laboratory testsand easy access to and case management at a major hospital(SoeSoe Aye et al 2000).

Figure(5) Meningococcaemia rash of a 13 year old boy with meningococcal disease from MyaingTownship admitted to Station (rural) hospital, Kyardet,SalingyiTownship,Sagaing Division. Ecchymosis from left leg looked dark due to the application of gentian violet

The overall case fatality for the whole union cases was 8.5%.Outbreaks occurred from January up to July and then sporadic cases occurred afterwards in the year 2000(Figure.6). Distribution of outbreak area in the central dry zone of Myanmar was shown in the figure.7

Laboratory diagnosis

Out of 282 cases admitted to Mandalay General Hospital, 279 (99%) cases had examination of cerebrospinal fluid and positive for Gram stain (intracellular Gram negative diplococci detected) and positive for latex agglutination (N.meningitidis group A positive).( SoeSoe Aye et al,2000) (2)Isolation of organisms was made for a few cases by the Public health Laboratory, Mandalay.

Figure. (6) Monthly cases and deaths of Meningococcal diseases in Myanmar, 2000

Figure. (7) Distribution of cases of Meningococcal diseases in Central Dry Zone of Myanmar, 2000

Discussion

Neisseria meningitidis (the meningococcus) is a leading cause of meningitis and fulminant septicaemia and a significant public health problem in most countries. Globally, about 5000 000 cases and 50,000 deaths are caused by this pathogen each year(WHO, Weekly Epidemiological Record, 2002). Epidemics of meningococcaldisease are recurrent in that part of sub-Saharan Africa known as the“meningitis belt,” which extends from Senegal in the west to Ethiopia in the east(Riedo FX, Plikaytis BD, Broome CV. 1995) Age and race-adjusted projections of the U.Spopulation suggest that approximately 2,600 cases of meningococcal disease occurred annually in the UnitedStates(Center for Diseases Control, USA, 1993). Recently outbreak occurred in New Dehli, India andas of 16 May 2005, 303 cases, with 26 deaths, of meningococcal disease have been reported in Delhi, India.(12) The majority of cases and all deaths have occurred in young adult populations, in people aged between 16 and 30 years. (WHO, 2003) The presence of Neisseria meningitides serogroup A in cerebrospinal fluid was demonstrated in 18 cases.

As a rule, endemic disease occurs primarily in children and adolescents, with the highest attack rates in infant age 3-12 months, whereas in meningococcal disease epidemics, rates may rise in older children and young adults. In sub-Saharan Africa, endemic and epidemic disease strike primarily children and adolescents (WHO, 2002). In outbreaks in Myanmar, all age groupswere affected and more in 5-9 year age group. Male to female ratio was 1.45 in our cases while it was 1.51 in Niamey, Niger in Africa from 1981-1986. (G. Campagne, A. Schuchat, S. Djibo,1999)(11)

Most untreated cases of meningococcal meningitis and/or septicaemia are fatal. In industrialized countries, the overallmortality frommeningococal meningitis is usually 5 % to 10 % and closer to 10% in Africa. Case fatality rates in fulminant septicaemia may exceed 15 % to 20 %. The overall case fatality rate in Myanmar was less than10% in recent years. About 10 % to 15 % of those surviving meningococcal meningitis will suffer from significant neurologic sequelae, including mental disorders, deafness, palsies and seizures. Extensive tissue necrosis, sometimes resulting in amputations, may also occur. Sequelae are infrequent in patients in Myanmar. The disability was 2 % in the Mandalay outbreak in 2000. (SoeSoe Aye et al, 2000) Sequelea and disability were also noted in previous outbreaks.(Ye Myint, Aye Min, 1992)(6)The proportion of acute meningococcaemia varied from outbreak to outbreak and is usually less than 10 per cent(B.MGreenword. 1994).(10)Inthe outbreak of 1999 the rate was 4 per cent.

The diagnosis of meningitis (P.F Wright, 1989)is dependent on not only the physician’s skill and motivation, but also the performance of a lumbar puncture and the laboratory’s capability to examine and culture the cerebrospinal fluid (CSF).(7)In the very early period of meningococcal disease outbreak, diagnosis was made mainly as suspected cases due to reluctance to perform lumber puncture and lack of diagnostic materials.Neutrophil leucocytosis of peripheral blood was observed in some cases.Bacterial Meningitis score that originally predict bacterial meningitis could be used in reverse manner. (Lise E. Nigrovic et.a.l 2007)(8) The lack of following criteria;positive CSF Gram stain, CSF absolute neutrophil count (ANC) of at least 1000 cells/µL, CSF protein of at least 80mg/dL, peripheral blood ANC of at least 10 000 cells/µL and a history of seizure before or at the time of presentation classifies patients at very low risk of bacterial meningitis. Cerebrospinal fluid cytology and chemistry can be used to define a case as bacterial meningitis. Turbid CSF with or without positive Gram stain suggest probable cases according to the case definition.Lumbarpuncture is necessary to confirm the diagnosis of purulent meningitis and to identify meningococci (and exclude other common causative pathogens such as pneumococcus and H. influenzae). Accurate surveillance for meningococcal disease was required to detect trends in patient characteristics, antibiotic resistance and serogroup-specific incidence. Laboratory–based surveillance (Lisa A. Jackson, Jay D. Wenger, 1993)for meningococcal diseases was done in selected areas of United States from 1989 to 1991.(9)

Enhanced or reinforced epidemic meningitis surveillance that was currently implemented in African meningitis belt, focused on weekly collection, compilation and analysis, transportation of laboratory specimens (WHO 2005). Due to enhanced laboratory surveillance, an unprecedented number of cerebrospinal fluid (CSF) samples had been collected in the past 3 years, allowing a broader view of pathogen distribution.

With regard to outbreak management and control, increasing community awareness of the public and efficient management of the cases after getting the outbreak diagnosis are the crucial factors to interrupt the transmission and spread. The attack rate of two adjacent townships, Thabeikkyin and Moemeik,(94 versus 235) was found to be different due to timeliness in outbreakdetection,andcase management but the hospital staff of both Thabeikkyin and Moemeik was observed to be efficient in response to the very unusual emergency situation for a small hospital. (Ye Hla et al, 2000)Outbreaks remained unnoticed and unreported in MoemeikTownship for a period of one or two weeks.

Epidemic pattern of the diseases was observed during the years of outbreak that lasted from 1992 to 2004. (Ye Myint, Ye Hla, SoeLwinNyein2004) al)Aswas demonstrated by the present study,enhanced surveillance and effective case management was the mainstay of control of outbreaks of meningococcal diseases.

References

1. Saw Myint, Ye Myint, Ye Hla,SoeLwinNyein:Reports on Outbreak investigations of meningococcal diseases, Central Epidemiology Unit, Department of Health
2. SoeSoeAye, T.Tun, Y.Yi, Ye Hla, K.M.Htoon.,C.K Tin, Meningococcal infection at children hospital and Mandalay division, Children Hospital, Mandalay, Department of Health, Mandalay Division, Public Health Laboratory, Central Epidemiological Unit, Yangon, Paper read at Myanmar Medical Conference,2001
3. WHO, Lyon, FoundationMerieux, 1995,Guidelines on Control of epidemic meningococcal disease,
4. YeHla, ed. Case definition for surveillanceof communicablediseases, recommended guidelines, 2002, Central Epidemiological Unit, Department of Health, and Ministry of Health
5. MoeSwe, Outbreak report of Meningococcal diseases in MoemeikTownship in 1999, Assignment report for Field Epidemiology Training Programme, Ministry of Public Health, Thailand, 2000, unpublished
6. Aye Min, Team Leader, Vector Borne Diseases Control, Magway Division, Outbreak report of Meningococcal diseases in Htilin, 1992
7. P.F Wright. Approaches to prevention of acute bacterial meningitis in developing countries, Bulletin of World health Organization, 67(5); 479-486 (1989)
8. Lise E. Nigrovic et al, Clinical Prediction Rule for Identifying Children with Cerebrospinal Fluid Pleocytosisat Very Low Risk of Bacterial Meningitis, Journal of American Medical Association,Vol.297 No.1, January 3,2007
9. Lisa A. Jackson, Jay D. Wenger,Laboratory-Based Surveillance for Meningococcal Disease in Selected Areas, United States, 1989–1991MMWR 1993; 42 (No. SS-2):21–30.
10. B.M Greenword. Meningococcal infection.Oxford Textbook of Medicine, Oxford University Press. 1994
11. G. Campagne, A. Schuchat, S. Djibo, Epidemiology of bacterial meningitis in Niamey, Niger, 1981-96.Bulletin of the World Health Organization, 1999, 77 (6) World Health Organization 1999 499-508.
12. World Health Organization Geneva. Weekly epidemiological record No. No. 20, 2005, 80, 177–178. Outbreak news- Meningococcal diseases, India
13. World Health Organization Geneva, Enhanced surveillance of epidemic meningococcal meningitis in Africa: a three-year experience. Weekly Epidemiological Record, No.37, 2005, 80,313-320

Ye Hla¹, SoeLwinNyein ,²Tin TinAye², Yi Yi^{3 1}Department of Medical Research (Central Myanmar),
²Department of Health,PublicHealth Laboratory,Mandalay³