AN OUTBREAK OF MENINGOCOCCAL DISEASE IN GLOUCESTERSHIRE

558

AN OUTBREAK OF MENINGOCOCCAL DISEASE IN GLOUCESTERSHIRE KEITH A. V. CARTWRIGHT JAMES M. STUART NORMAN D. NOAH Public Health Laboratory, Gloucester, Gloucester Health Authority; and Communicable Disease Surveillance Centre, Colindale

Between October, 1981, and March, 1986, there were 65 cases of meningococcal infection, about five times the expected number, in Gloucester Health District. The cases, mainly in teenagers and young adults, were clustered in the Stroud district and in the southern part of Gloucester City, and most were caused by a sulphonamide-resistant group B type 15 meningococcus. 2 patients died. Only 57% of meningitis 7 (11%) patients had cases were formally notified. septicaemia without meningitis, not a notifiable disease. All meningococcal disease should be made notifiable and meningococci should be serotyped routinely so that the epidemiology of the disease can be monitored before the introduction of suitable vaccines.

Summary

INTRODUCTION

SINCE 1940, when there were over 12 000 notifications in England and Wales, meningococcal disease has been much less common. Following the last peak in 1974 (1296 notifications) the annual number of notifications declined steadily until 1984, when 401 cases were notified. In 1985, 549 cases were notified and the rise has continued into the first quarter of 1986.1 During the first half of this century, group A organisms were responsible for major outbreaks of meningococcal disease in England and Wales. Since 1970 group B strains have predominated to an increasing degree and now account for about 60% of infections.2 The introduction by Frasch of a typing system for the protein surface antigens in the early 1970s3 increased the potential for epidemiological investigation. In 1974/75 60% of group B isolates tested in England and Wales were type 2. The prevalence of this type has since declined while that of type 15 organisms has risen from 15% of all group B strains in 1979 to 56%in 1985

(Jones DM, personal communication). Meningococcal disease in Stroud, Gloucestershire, conformed

to

a rural district in the national pattern until

Bay D, Aasen S, Lystad A. Meningococcal disease in Norway 1980-1983 Natl Inst Publ Hlth Ann (Oslo) 1983; 6: 151-53. 19. Frøholm LO, Holten E, Poolman JT, Zollinger WD. Typing of Norwegian isolates and possible implications for serogroup B vaccination. In: Schoolnik GK, ed. The pathogenic neisseria. Washington DC: ASM, 1985: 541-45. 20. Peltola H, Jónsdóttir K, Lystad A, Sievers CJ, Kallings I. Meningococcal disease in Scandinavia. Br Med J 1982; 284: 1618-21. 21. Zanen HC. Meningokokken ziekte in Nederland; na eb weer vloed? Ned T Geneesk 1984; 128: 515-18. 22. De Marie S, Poolman JT, Hoeijmakers JHJ, Bol P, Spanjaard L, Zanen HC. Meningococcal disease in the Netherland, 1959-1981: the occurrence of serogroups and serotypes 2a and 2b in the Netherlands. J Infect 1986; 12: 133-43 23. Abbott JD, Jones DM, Painter MJ, Young SEJ. The epidemiology of meningococcal infections in England and Wales 1912-1983. J Infect 1985; 11: 241-58. 24 Zollinger WD, Moran EE, Connelly H, Mandrell RE, Brandt B. Monoclonal antibodies to serotypes 2 and serotype 15 outer membrane proteins of Neisseria meningitidis and their use in serotyping. Infect Immun 1984; 46: 260-66. 25. Mocca LF, Del Real G, Frasch CE. Serotypes and polyacrylamide gel electrophoresis types among disease-associated isolates of group B Neisseria meningitidis in Spain, 1976-1979. J Infect Dis 1983; 148: 249-53. 26. Cannon JG, Black WJ, Nachamkin I, Stewart PW. Monoclonal antibodies that recognize an outer membrane antigen common to the pathogenic Neisseria species but not to most nonpathogenic Neisseria species. Infect Immun 1984; 43: 994-99.

1982, when the isolation of

a

sulphonamide-resistant

marked the beginning of an outbreak. A surveillance scheme was set up to record all cases of meningococcal disease in residents of Gloucester Health District (population 301537) from October 1, 1981. (Population figures cited in this paper are taken from the 1984 estimates of the Gloucestershire County Planning Department.) This report includes all cases recorded up to March 31, 1986.

meningococcus

METHODS

Case definition.-A patient was designated a case when Neisseria meningitidis was isolated from the blood and/or cerebrospinal fluid (CSF), or gram-negative diplococci were seen in the CSF, or clinical signs of meningitis or septicaemia were accompanied by a

haemorrhagic rash.

Case details.--Cases were identified from statutory notifications and Public Health Laboratory (PHL) records. In addition, informal enquiries were made of adjacent health districts. General practitioners (GPs) were asked to report all cases known to them. The Hospital Activity Analysis (HAA) system was checked for all deaths or discharges with a diagnosis of meningococcal infection (International Classification of Diseases, 9th revision, code 036). Mortality statistics produced by the Office of Population Censuses and Surveys were checked for deaths due to meningococcal infection. Clinical features, complications, and outcome were obtained from hospital records. Microbiology.-Strains of meningococci isolated were grouped and tested for sulphonamide sensitivity at Gloucester PHL. From March, 1983, serogroup and sulphonamide sensitivity results were confirmed at the PHLS Meningococcal Reference Laboratory (MRL), Manchester, where strains were also serotyped. Management.-As the outbreak developed an advisory group coordinated by the Medical Officer for Environmental Health (MOEH) was set up; it included representatives from the Communicable Disease Surveillance Centre and the MRL. RESULTS

Epidemiology of meningococcal infection were identified in the 4!years March 31,1986. Only half the cases (33/65) were formally notified; the remainder were ascertained through PHL records. If the national notification rate for meningococcal meningitis had applied in Gloucester Health District during this period the number of notified cases would have been 12. The HAA and GP enquiries yielded no additional cases. Between 3 and 5 cases were reported in most quarters, with a peak of 12 in the last quarter of 1983 (fig 1). Over the 4 zyear period the number of cases recorded 65

cases

to

18.

Fig

1--Quarterly incidence Gloucester Health District.

of

meningococcal

infection

in

559 TABLE I-MENINGOCOCCAL INFECTION BY LOCAL AUTHORITY WITHIN GLOUCESTER HEALTH DISTRICT IN YEARS TO MAR 31,

4

1986

Notification rate in

England and Wales/100 000/annum (1982-85)

=

Microbiology Neisseria meningitidis was isolated from 56 of the 65 patients (table III). In another 6 patients gram-negative diplococci were seen on microscopical examination of the CSF but not obtained on culture; in 3 patients the diagnosis was made on clinical grounds. 38 of the 49 known group B strains (76%) were sulphonamide resistant. 33 organisms, including two group C strains, expressed the Frasch 15

0-9.

in the third quarter of a year (1 -8) averaged less than half that seen in each of the remaining three quarters (4-2, 4-0, 42); this seasonal pattern is similar to that seen nationally. Of the three local authority districts, only Stroud and Gloucester had attack rates higher than expected (table i). The disease seemed to travel slowly through discrete communities within a district. The town of Nailsworth (population 5453), four miles south of Stroud was affected in 1982 and 1983. In 1983 and 1984 Stroud itself (population 20 642) was the main focus of cases while in 1985 and 1986 Stonehouse (population 6612), situated three miles west of Stroud, had the highest attack rate. Cases occurred steadily, albeit at a lower rate in the southern half of Gloucester City, throughout the study period. The only large village in the Stroud district free of the disease was Painswick (population 3163), four miles north of Stroud. The attack rate was highest in teenagers and 71 % of the cases (46/65) were aged between 10 and 24 (fig 2). Only 1 case occurred in an infant. Males outnumbered females 1 4:1 (38:27). Two pairs of cases occurred within family groups. One secondary school in Nailsworth had a total of 5 cases amongst pupils in the first 2 years of the outbreak. Only three other schools had more than 1 case.

TABLE

ADH

=

II-SEQUELAE OF INFECTION

antidiuretic hormone.

TABLE III-BACTERIOLOGICAL DETAILS OF MENINGOCOCCAL

ISOLATES

Clinical Features 58 patients had meningitis; 7 had septicaemia without evidence of meningeal inflammation. The average inpatient stay for the survivors was 12-9 days (range 7-t8). 8 patients had serious permanent sequelae and 20 had temporary complications (table II). 2 boys aged 16 and 12 died; both had been ill for only a few hours and in both necropsy revealed meningitis and septicaemia.

antigen (table ill). Group B type 15 sulphonamide-resistant (B:15 R) strains predominated from the start of the outbreak. From April, 1985, the introduction of type 16 antiserum by the MRL enabled 7 out of the 10 subsequent group B isolates to be identified as B:15:P1.16 R organisms. 7 group C strains were isolated, of which 3, including one C:15:P1.16 R organism, were sulphonamide resistant.

Fig 2-Age-distribution of meningococcal infection in England and Wales and Gloucester Health District.

In the first of the two instances in which 2 cases occurred in the same family, B:15 R strains were isolated from two sisters admitted within 48 h of each other. In the second instance aB:15:P116R strain was isolated from a young boy with meningitis and a B:15 R organism from his sister, who also presented with meningitis 1 month later, despite having had rifampicin prophylaxis when her brother’s illness was diagnosed. At the time this girl fell ill B: 15 R organisms were also isolated from throat swabs taken from the index case and his mother. When 2 cases occurred within a short period in one school (1 due to a C: 15 R strain and the other yielding no organism), about 220 pupils and staff were swabbed three times at weekly intervals. No C:15 R, B:15 R, or B:15:P1.16 R

organisms

were

found, although

9

sulphonamide-resistant

560

strains that were either non-groupable or of group C were isolated. 7 of these 9 strains expressed the 15 antigen and 3 the 16 antigen as well. In another school attended by a patient with B:15 R meningitis 104 individuals were swabbed. No B:15 R or B:15:P1.16 R strains were isolated though two B:15 sensitive strains were found.

Management of the Outbreak An informal notification system was set up between hospital medical staff, the PHL, and the MOEH. Details of suspected cases were entered in a meningitis register on admission and were regularly updated. Household and kissing contacts of each case were given rifampicin prophylaxis on confirmation of the diagnosis. No rifampicin-resistant strains were isolated from cases or contacts.

In the absence of any definable closed community neither prophylaxis nor swabbing and selective prophylaxis is indicated (PHLS Communicable Disease Surveillance Centre, unpublished) and these were, therefore, not undertaken. The swabbing exercises described above were done to investigate meningococcal carriage rates. General practitioners were informed of the progress of the outbreak every 6 months and were encouraged to give parenteral benzylpenicillin before arranging for hospital admission if a diagnosis of meningococcal infection was suspected. There was a record of antibiotics being given before hospital admission in only 6 cases. The media contributed to heightened public anxiety by usually exaggerated and often inaccurate reporting. We received many enquiries from people concerned about visiting or moving into the area. The combination of raised awareness in both the public and in general practitioners resulted in increased numbers of people with headache attending surgeries or being admitted to hospital. As the outbreak progressed the number of diagnosed cases of viral meningitis rose from 4 in 1982 to 22 in 1985, a total of 38 in the study period; of these 27 (71%) were from Stroud district. mass

DISCUSSION

Infections due

B:15 R meningococci are becoming in the UK, but this is the largest increasingly outbreak due to this organism yet described in the country. Several features of the outbreak are of importance. First, there is no evidence, after 4 Zyears, that the outbreak is waning. In Norway, over the 11-year period from 1974 to 1984, the average annual incidence of meningococcal disease remained raised (74 cases/100 000), with B:15 R organisms predominating.4 Recent localised outbreaks due to group B strains in England and Wales have lasted from 8 months to to

common

3years.2,s,6 Secondly,

the age-distribution of cases is unusual by comparison with recent national data (fig 2). Meningococcal disease usually affects children under the age of 5 years, a reflection of the low antibody levels in this age-group.’ The high attack rate in teenagers and young adults by the B: 15 R strain of meningococcus has also been recorded in Norway* but the absence of a peak in young children in the Gloucestershire outbreak is unexpected. Thirdly, throat swabbing revealed a very low carriage rate of B:15 R meningococci in symptomless contacts. Similar low carriage rates of this organism were found in an extensive swabbing investigation in Somerset after a minor outbreak in 1985-86 (Bowie C, personal communication)

during investigation of a school outbreak in London (Cann K, unpublished). There are two possible explanations for the low carriage rate. B:15 R and B:15:PLI6 R strains may be of high virulence and low transmissibility, or they may be of low virulence and high transmissibility but with an extremely short period of carriage. The slow movement of the disease through the Stroud communities and the persistently high and

after 4!years are consistent with the first The susceptibility of teenagers to B:15 infections may be due to their high level of social activity, which offers an opportunity for transmission of meningococci. Such spread contrasts with that of meningococci in other outbreaks, in which the organism usually passes through a family to cause disease in the younger children 6,9 The case-fatality rate in this outbreak (3%) was lower than those reported in recent English outbreaks, which have ranged from 14% to 19%.2,5,6 The overall case-fatality rate was 9% in England and Wales between 1975 and 1983,9% in Scotland between 1972 and 1982,10 and 11 % in Norway between 1974 and 1984.’ The predominance of infection in teenagers, in whom the case-fatality rate is usually low,2 may partly account for the low mortality but early case referral and prompt hospital treatment may well have been important factors.ll,12 In addition, the efficient informal notification system may have boosted the number of non-fatal cases identified. Doubts have been expressed recently about the need for and safety of lumbar puncture in patients with suspected meningitis." In the patients affected in this outbreak, examination of CSF was much more successful (51/57 film or culture positive) than blood culture (27/51 culture positive) in establishing the diagnosis, and CSF microscopy provided immediate confirmation of the diagnosis in 42/57 cases. Raised intracranial pressure was the main reason for not doing a lumbar puncture in the remaining 15 cases. Coning following lumbar puncture was suspected in 1 case only and the patient made a good recovery. The epidemiology was complicated; 12 different meningococcal strains were identified yet they all affected the same age-groups. The isolation of so many different strains of meningococci from a fairly homogeneous clinical and epidemiological group raises the possibility that there may be variability in the expression of surface antigens and/or sulphonamide resistance in meningococci or that interchange of genetic material between strains is occurring. There may be a determinant for virulence closely associated with either the gene coding for sulphonamide resistance or that coding for the type 15 antigen. Since 1968 notification of meningococcal infection in England and Wales has been restricted to meningitis. There seems to be no logic behind the decision to exclude septicaemia, which only serves to confuse attempts at epidemiological investigation. 11 % of cases in this outbreak were diagnosed as having septicaemic illness without meningitis and were therefore not, by statute, notifiable. Of attack

rate

explanation.

the

remaining cases only 57% were formally notified, a proportion similar to that of other reports,14 despite high amongst doctors. Accurate notification and typing of meningococci are essential pre-requisites for the development and implementation of a surveillance and immunisation programme. The increasing numbers of group B sulphonamide-resistant meningococci now being isolated in awareness

561 this country, the ability of these organisms to maintain high endemic levels of disease, and the lack of effective preventive measures emphasise the need for vaccine development. It is, therefore, important that all meningococcal disease should be made notifiable, that the notification system should be supplemented by an efficient link between the microbiologist and the MOEH, and that all pathogenic isolates of meningococci should be both grouped and

serotyped. ADDENDUM

In the second quarter of 1986 there have been a further 9 and 1 death. Group C organisms were isolated from 5 cases and B:15:P1.16 R strains from 3.

cases

We thank Dr D. M. Jones, PHLS Meningococcal Reference Laboratory, for typing strains of meningococci, for helpful discussions and, together with other colleagues, for comment on this paper; we also thank our clinical colleagues for permission to report on patients admitted under their care.

Correspondence should be addressed to K. A. V. C., Public Health Laboratory, Gloucestershire, Royal Hospital, Great Western Road, Gloucester GL1 3NN.

Biomedical Research

REFERENCES 1.

Report from the PHLS Communicable Disease Surveillance Centre. Br MedJ 1986; 292: 1447-48.

JD, Jones DM, Painter MJ, Young SEJ. The epidemiology of meningococcal infections in England and Wales 1912-1983. J Infect 1985; 11: 241-57. 3. Frasch CE. Noncapsular surface antigens of Neisseria meningitidis. In: Weinstein L, Fields BN, eds. Seminars m infectious disease, vol II. New York: Stratton Intercontinental, 1979: 304-37. 4. Bovre K. Meningococcal disease in Norway. Antonie van Leeuwenhoek (in press). 5. Easton DM, Estcourt PG, Brimblecombe FSW, Burgess W, Hass L, Kurtz JB. Outbreak of meningococcal disease in Devon. Br Med J 1974, i. 507-09. 6. Farries JS, Dickson W, Greenwood E, Malhotra TR, Abbott JD, Jones DM. Meningococcal infections in Bolton, 1971-74. Lancet 1975; ii: 118-21. 7. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus I. The role of humoral antibodies. J Exp Med 1969; 129: 1307-26. 8. Bay D, Aasen S, Lystad A. Meningococcal disease in Norway 1980-83. NIPH Ann 1983; 6: 151-53. 9. Munford RS, Taunay A de E, de Morais JS, Fraser DW, Feldman RA. Spread of meningococcal infection within households. Lancet 1974; i: 1275-78. 10. Fallon RJ, Brown WM; Lore W. Meningococcal infections in Scotland 1972-82. J Hyg Camb 1984; 93: 167-80. 1 1. Slack J. Deaths from meningococcal infection in England and Wales in 1978. J R Coll Phys Lond 1982; 16: 40-44. 12. Oakley JR, Stanton AN. Meningococcal infections during infancy: confidential inquiries into 10 deaths. Br Med J 1979; ii: 468-69 13. Richards PG, Towu-Aghantse E. Dangers of lumbar puncture. Br Med J 1986; 292: 605-06. 14. Goldacre MJ, Miller DL. Completeness of statutory notification for acute bacterial meningitis. Br Med J 1976; ii: 501-03. 2. Abbott

CRITERIA OF ELIGIBILITY FOR FUNDING

its BIDs, and by means of several grant the NIH also engages in scientific collaborations with foreign institutions and international organisations, and it may make awards to US investigators whose work involves substantial collaboration with foreign institutions. Subject to the laws of the applicant’s country, private, public, for-profit, or non-profit foreign institutions are eligible for NIH grant support; the criteria for eligibility unusual are talents, resources, populations, or environmental conditions that are not readily available in the United States or that augment existing US resources. In addition, a foreign application must have specific relevance to the mission and programme objectives of the awarding BID and must have significant potential for advancing health-related science in the US.

Through

NATIONAL INSTITUTES OF HEALTH AWARDS TO INSTITUTIONS IN FOREIGN COUNTRIES, 1976 - 85 ANTONIA C. NOVELLO General Medicine B Study Section, Division of Research Grants, National Institutes of Health, Bethesda, Maryland 20892, USA are eligible for grants from the US National Institutes of Health (NIH) for biomedical research. Applications undergo a two-tier process of peer review. Most applications are approved and about a third succeed in obtaining funding. Each year the NIH awards about 300 research grants and contracts to foreign institutions and supports another 100 international research fellows. In the fiscal year 1984, the NIH spent about $35 million on these awards—about half the amount that it spent on international activities.

Summary

Foreign institutions

INTRODUCTION

THE Public Health Service (PHS) of the United States of America awards grants and contracts for biomedical and behavioural research as part of its overall mission to improve health. The National Institutes of Health (NIH), as an agency of the PHS, is the main source of funding for health-related research in the USA. The agency is further divided into 20 organisational components, which are subdivided in turn into 4 bureaus, 9 institutes, 6 research and support divisions, and a National Center for Nursing Research. These NIH bureaus/institutes/divisions (BIDs) are engaged in a broad and complex variety of scientific activities. Monies allocated annually to the NIH by the US Congress are used to fund activities which are broadly divided into intramural and extramural activities. The extramural portion goes to funding research and research training primarily at institutions of higher education and research institutes, by a variety of grant mechanismsgrants, contracts, training grants, fellowships, and cooperative agreements. The type of research supported ranges from the most basic to the applied and clinical.

instruments,

GRANT MECHANISMS

A foreign applicant may apply through his or her institution for the commonest type of NIH grant, the research project grant or R01. Foreign institutions may not be awarded grants for programme projects, centres, resources, or for training supported by USPHS National Research Service Awards. Likewise, grants cannot be awarded to individuals as grantees in foreign countries or be transferred to or between foreign institutions. Grants may, however, be made for international conferences, for collaborative efforts through - research and development contracts, and for international research fellowships (see below). Although most research project awards are made to domestic institutions, 50 to 80 competing grants a year go to foreign institutions. THE APPLICATION AND ITS REVIEW

be in English, on form PHS 398, available from the Office of Grants Inquiries, Division of Research Grants (DRG). All new research or conference grant applications are processed in batches, according to date by which an application is received (table I). Proposals should be scientifically worthy, methodologically sound, and clearly and cogently presented.l-4 Applicants who do

Applications

must