Childhood tuberculosis and tuberculous meningitis: high incidence rates in the Western Cape of South Africa S. Berman*, M. A. Kibel*, P. B. Fourie+, P. M. Strebelt “Depurtment of Paediatrics and Child Health, University of Cape Town, South Africa, f MRC Nationul Tuberculosis Research Programme, Pretoria, and$ MRC Centre for Epidemiological Research in Southern Africa Cape Town, South Africu
S U M M A R Y. In recent years higher incidence rates of tuberculosis (TB) have been reported from the Western Cape than from other health regions of South Africa. In contrast to the various pulmonary forms of tuberculosis, tuberculous meningitis (TBM) always requires hospital admission, and can thus be used as an indicator of the extent of the infection in a community, as well as providing a measure of the effectiveness of primary and secondary preventive measures. In the present study an attempt was made to identify all cases of tuberculous meningitis aged 14 years and younger which occurred in the region, by checking notifications and the records of all hospitals, and verifying diagnosis against set criteria. Rates for the entire period were calculated according to updated census data. There was a total of 689 confirmed cases, of which only 55% had been notified. Of the 238 cases confirmed in the 3-years period, 1985-1987,25.2% were under 1 year, 51.7% under 2 years, and 79.8% under 5 years of age. Age-specific incidence per 100 000 children were respectively 31.5 (O-l years), 17.1 (l-4 years), 4.8 (5-9 years), and 0.7 (10-14 years). Rates in rural areas were far higher than in metropolitan regions. Utilizing tuberculin test data and total notifications, the following risks could be calculated for ‘Coloured’ children (of mixed race) aged o-4 years: 2-3% annual risk of infection; 15.7% risk of TB in infected population; 0.5% risk of TBM in infected population; 0.9% risk of TB in children aged 5-14 years; 0.01% risk of TBM in children aged 5-14 years.
k . Dans les an&es recentes les taux d’incidence de la tuberculose signales au Cap Ouest ont et6 plus &eves que ceux signal& dans les autres regions sanitaires d’Afrique du Sud. A l’inverse des differentes formes pulmonaires de la tuberculose (TB), la meningite tuberculeuse (TBM) necessite toujours une admission a l’hopital, et peut done &treutilisee comme un indicateur de l’etendue de l’infection dans une communaute, en m$me temps qu’elle fournit une mesure de l’efficacite des mesures de prevention primaire et secondaire. Au tours de la presente etude on a tent& d’identifier tous les cas de meningite tuberculeuse apparus dans la region chez des sujets LgCsde 14 ans et moins, en examinant les notifications et les registres de tous les h8pitaux et en verifiant les diagnostics par rapport a des criteres prC-Ctablis.Les taux pour l’ensemble de la periode ont CtC calcules a partir des chiffres mis a jour du recensement. 11y avait un total de 689 cas confirmCs dont seulement 55% avaient Cte notifies. Sur le total des cas, 25,2% Ctaient lges de moins d’un an, 51,7% de moins de 2 ans et 79,8% de moins de 5 ans. L’incidence selon l’age, pour 100 000 enfants, Ctait de 31,5 (0 a 1 an), 17,l (2 a 4 ans), 4,8 (5 a 9 ans) et 0,7 (10 a 14 ans). Les taux provenant des regions rurales Ctaient bien plus Cleves que ceux de la region metropolitaine. En utilisant les donnees du test tuberculinique et le total des notifications, les risques suivants ont pu Ctre calcules pour les enfants ‘m&is (de race mixte) LgCsde 0 a 4 ans: risque annuel d’infection de 2 a 3% ; risque de tuberculose dans une population infectbe, 15,6% ; risque de TBM dans une population infectee, 0,5% ; risque de TB chez des enfants LgCsde 5 a 14 ans, 0,9% ; risque de TBM chez des enfants Igb de 5 a 14 ans, 0,Ol %.
R k S UM
R ES U M E N . En 10s ultimos adios las tasas de incidencia de tuberculosis informadas por Western Cape han sido miis elevadas que en otras regiones de Africa de1 Sur. Contrariamente a las diversas formas de tuberculosis pulmonar (TB), la meningitis tuberculosa (MTB) requiere siempre una hospitalizaci6n y de esta manera puede
Correspondence to: Professor M. A. Kibel, Department of Paediatrics and Child Health, Child Health Unit, Children’s Centre, 46 Sawkins Road, Rondebosch 7700, South Africa. 349
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Tubercle and Lung Disease
ser utilizada coma un indicador de la extensi6n de la infection en la comunidad y para medir la eficacia de las actividades de prevenci6n primaria y secundaria. En el presente estudio se intent6 identiflcar todos 10s cases de MTB en nifios de 14 adios de edad o menos detectados en la region, revisando las declaraciones y 10s registros de todos 10s hospitales y verificando el diagn6stico con respect0 a criterios preestahlecidos. Las tasas para el period0 complete fueron calculadas utilizando datos actualizados de1 censo. Se encontro un total de 689 cases confirmados, de 10s cuales ~610el55 % habia sido declarado. Del total de cases, el25,2 % tenia menos de 1 auo de edad, el51,7 % menos de 2 adios y el79,8 % menos de 5 adios. La incidencia especifica por grupos de edad por 100 000 niiios era: 31,5 (O-l aiio), 17,l (2-4 adios), 4,8 (5-9 adios) y 0,7 (10-14 adios). Las tasas en las regiones rurales eran mucho mis elevadas que en las regiones metropolitanas. Utilizando 10s datos de la prueba tuberculinica y el total de declaraciones, se pudo calcular un cierto numero de riesgos para 10s nifios ‘mestizos’ (de raza mixta). Para 10s niiios de e4 adios: 2-3 % de riesgo de infecci6n anual, 15,6 % de riesgo de TB en la problaci6n infectada, 0,5 % de riesgo de MTB en la problacion infectada; para 10s nifios de 5-14 adios: 0,9 % de riesgo de TB; para 10s niiios de 5-14 adios: 0,Ol % de riesgo de MTB.
INTRODUCTION Worldwide interest in tuberculosis (TB) has been reawakened by the epidemic of acquired immunodeficiency syndrome (AIDS) which is currently threatening the global tuberculosis situation. This is especially relevant in developing countries where there is a high prevalence of infection with Mycobacterium tuberculosis, such as in Africa.’ In South Africa, TB has been a problem only since the 19th century when immigrants, many of whom were seeking a favourable climate to recover from consumption, arrived from various parts of Europe.’ Notification of TB was started in 1922. A gradual increase in reported incidence was then noted, which reached an alltime high in the mid-1960s with a rate around 350/100 000 of the general population. By 1986 the incidence rate had declined to around 200/100 000,3 and has remained at this level since (237/100 000 in 1990).4 There has, however, been an increase in tuberculosis notifications from the Western Cape Health Region (WCHR): one of the three health regions in the Cape Province. This region, with a total population of approximately 3 million in 1986, includes Cape Town and environs and has traditionally been inhabited by White people and people of mixed ethnic origin (so-called ‘Coloured’). In the last 20-30 years a major influx of rural Black families has taken place, particularly into the peri-urban areas of Cape Town. They have carried with them the experience of high TB prevalence from their place of origin. In 1986, for example, the respective total TB incidence rates for Coloured and Black populations were 628 and 976 per 100 000 in the WCHR, compared with an average of 280 and 315 per 100 000 for the rest of the country.5 Differences in case-finding and reporting practices may partially explain this discrepancy, but would be unlikely to result in rates approximately 3 times higher than elsewhere. Tuberculous meningitis (TBM) has long been recognized as a problem in the WCHR. In 1950 an epidemiological study on TBM was carried out in what was then known as the Western Province of the Cape of Good Hope.6,7 This showed 163 cases of TBM originating
from the Cape Peninsula and 37 cases from various towns in the rest of the area over a 13-month period. Using these counts and population denominator figures derived from census data available for the time period, an incidence rate of 98 per 100 000 population was calculated for Coloured children below the age of 15 years residing in the metropolitan area of Cape Town. Further studies for the period 1979-1984 revealed that, whereas rates had dropped far below this figure, TBM was still a significant problem in the region.8,9x’0 Mortality was 24%,8 and there was a high occurrence of cerebral palsy (53%) and mental retardation (46%) among the survivors.” In an attempt to better understand the TB situation in the WCHR, we have looked at TB in childhood, as the annual infection and case rates of childhood TB, especially TBM, have significance as markers of the size of the infectious pool in the community.” The annual risk of infection, based on the estimated prevalence of infection according to skin test responses following tuberculin testing in young children, has been shown to be a useful indicator of the TB situation.” This relationship has been translated into an index referred to as the annual rate or risk of infection,” and has also been applied to children in most areas of Southern Africa, including the Western Cape.13 TBM, the most serious complication of childhood TB, is a relatively easily verifiable condition, as it always requires hospital admission and laboratory confirmation. As spontaneous recovery from TBM is virtually impossible without treatment, it provides a useful indicator of the extent of TB in the community, especially in areas of high tuberculosis prevalence.” Styblo has suggested that 1 case of TBM can be equated to 12 cases of smear-positive TB in the community.” The aims of the present study were three-fold: firstly, to determine the incidence of TBM over the period 1985-1987 in order to draw comparisons with previous studies; secondly, to assess the completeness of the registration system of TBM notifications; thirdly, to develop a model to predict risks of TBM in children infected with TB based on tuberculin skin test responses and total notifications. By estimating the proportion of infected children in a particular age group by tuberculin testing,
ChildhoodTB and TBM 35 I and combining this information with notification data from the same target population, the risk of TBM developing in this age group can be more accurately determined.
Incidence rates Rates for the entire period (1979-1987) culated according to updated census data.*
were recal-
Tuberculin skin test reactions and risk of infection PATIENTS AND METHODS Tuberculous meningitis Case jinding Information on all cases of TBM occurring within the WCHR over a 3-year period (1985-1987) was identified and pooled with data previously obtained for the years 1979- 1984.“,9 This entailed examining notifications records from the Department of National Health and Population Development. In addition all 75 hospitals in the area were canvassed for cases of TBM and folders were examined wherever possible. This allowed for checking of notification source data (by name, notifying authority, date, etc.) to determine the degree of under/over-reporting. Patients were regarded as resident in the WCHR if they had been living permanently within the defined area or had lived there for 6 months before illness; or if they had previously been resident in the area and had been referred for health care. Only children aged 14 years or younger at the time of diagnosis and diagnosed as having TBM between 1 January 1985 and 3 1 December 1987 were included. Time of diagnosis was taken as the time when treatment was started. Case dejinition Criteria for the establishment of a diagnosis of TBM were the same as for the previous two studiess.Y and required either: 1. Three or more of the following: (a) CSF pleocytosis and protein > 0.6g/l; (b) Evidence of TB, such as chest radiographic appearances, or sputum or gastric washings positive for Mycobacterium tuberculosis on culture, or a positive tuberculin skin test; (c) CSF culture-positive, or bromide partition ratio < 1.6 or CSF adenosine deaminate activity (ADA) > 5~0; (d) Clinical course consistent with TBM, or 2. Autopsy findings indicating TBM. Culture-positive cases (CSF or gastric washings) formed only a minority in our series. The above-mentioned case definition was the best we could come up with in an epidemiological study such as this, where cases were managed in a large number of hospitals. We thus required (I) at least 3 out of 4 of the following: (a) typical CSF, (b) evidence of TB elsewhere, (c) more specific CSF evidence and (d) clinical cause which in retrospect fitted the picture of TBM; or (2) autopsy evidence of TBM.
Tuberculin surveys in school children aged 5-14 years were carried out in Vredendal, Vredenburg/Saldanha and Swartland, all rural areas within the WCHR which have reported high TB rates. Mantoux testing was performed with 2 TU of Danish RT23 PPD containing Tween 80. Tests were read after 72 h with indurations measured transversely to the long axis of the forearm. In South Africa, BCG vaccination is given percutaneously by multiple puncture at birth, at school entry and at school leaving. Studies by Fourie & Kibel (unpublished) have shown that revaccination at school entry tends to produce significant tuberculin reactions lasting several years, sometimes without visible scarring. As much as 11% of Mantoux reactions measuring 10 mm or more in revaccinated children can be ascribed to BCG vaccination and not to natural infection. In our study, BCG scars were noted in 86% of children, and consequently, in order to limit as far as possible overestimation of natural infection prevalence because of BCGrelated reactions, calculations were based only on indurations from children without visible BCG scars. Prevalence of infection was calculated not on the basis of a cut-off point above which indurations were regarded as positive, but on the location of the mode of the frequency distribution. Measurable indurations tend to be approximately normally distributed in high TB prevalence communities. By adding twice the proportion of indurations measuring greater than the mode of the proportions of indurations at the mode, a better estimate is obtained than would be the case if the usual ‘greater or equal to 10 mm’ cut-off point is utilized. The expression employed was: (2 f.>mode + f. mode)/n where f. mode = frequency of indurations senting the mode f.>mode = frequency of indurations than the mode = number of observations n
repregreater
Total notifications of childhood tuberculosis Notifications of all forms of tuberculosis (ICD 010-018) in respect of children under 15 years of age from WCHR were obtained from the Department of National Health
*Baselinecensus data used came from the 1980and 1985 Central Statistical Services Population Census. (Reports Number 02-80-04 and 02-85-02). These needed to be adjusted due to under-enumeration. However, it is accepted that the Black population figures represent an undercount and. therefore, use was made of the projections of the population as set out by the Cape Town Metropolitan Transport Area of the City of Cape Town to determine a second population denominator.
352
Tubercle and Lung Disease
and Population 1985-1987.
Development
for
the
3-year
period
Table 1. Total numbers of cases of TBM by population WCHR, 1979-1987 Population
RESULTS Active surveillance of tuberculous meningitis Total numbers of cases of TBM in the WCHR for the entire period 1979-1987 in children under 15 years of age are shown in Table 1. The mean annual incidence rate per 100 000 children for the period 1985-1987 in Coloured children under 15 years of age was 9.0. The mean annual incidence rate for the same period and age group in Black children was 17.1, but after adjusting for population under-enumeration and excluding those cases intermittently resident outside of the study region, the incidence was 10.0. Figure 1 shows the age specific incidence of TBM in children for the whole of the WCHR (total population in age group as denominator, being based on census date) for the years 1985-1987. Most of the cases occurred in children under the age of 5 years (25.2% under 1 year; 51.7% under 2 years and 79.8% under 5 years). For the period 1985-1987, 68% of the cases were male and 32% female. For the same period there appeared to be no significant seasonal variation in numbers. Ongoing large-scale migration of the Black population in and out of the WCHR in recent years has resulted in a lack of the necessary demographic information required to conduct finer analysis of disease rates than those presented above. Furthermore, it is evident that TBM is
40
group
1982-1984(9)
1985-1987
Coloured Black White Asian
125 59 1 0
190 75 1 0
166 72 0 0
Total
185
266
238
not a significant problem among Whites and Asians. We have, therefore, restricted further analysis of incidence rates to the Coloured population only. Table 2 shows a comparison of the TBM incidence rates in the Coloured population (for the age group O-4 years) between the urban and peri-urban areas of Cape town and the rest of the WCHR, which consists largely of rural areas and small towns, These rates were obtained by dividing the average annual number of cases for each 3-year period with the average population denominator for that period. It will be seen that the rates for greater Cape Town are approximately half those of the rest of the region. The higher incidence in the predominantly rural areas is also demonstrated in the O-14 year age group. The mean annual TBM incidence rate per 100 000 Coloured children in the O-14 year age group for the entire period 1979-1987 is 5.9 for greater Cape Town compared to 10.8 for the rest of the WCHR. The mean ratio of TBM to all forms of TB in Coloured children under the age of 5 years, calculated over the same period (1979-1987), is also higher in the rest of the WCHR (7.0%) as compared to greater Cape Town (2.3%).
lncldenoe per 100 000
4.8
S-Q l-4 Age Groups (years) Fig. l-
1979-1981(8)
group in the
Age -specific incidence rates of TBM in children, WCHR, 1985-1987.
Childhood Table 2. according
TBM incidence rates in Coloured children aged O-4 years to region
1979-1981 1982-1984 19X5-1987
Notijcation
Region of greater Cape Town (per 100 000)
Rest of Western Cape Health Region (per 100 000)
12.0
21.3 30.9 29.0
18.9 13.6
of TBM
Of the TBM cases notijed during the period 1985-1987, 16% were excluded because of an incorrect diagnosis, a double notification or a clerical error. The remaining notified TBM cases formed 56% of the total number of TBM cases that had been verified for the period 1985-1987. While there was thus an under-reporting of 44%, the true error in under-reporting was less as the incorrect notifications would have been included in the notification statistics of the Department of National Health and Population Development. Of note is that of the 44% of cases that were not in the records of notifications, 15% were thought to have been notified according to medical records examined or doctors questioned. Of the 23 children notified as deaths, only 2 had been notified as cases while alive. Tuberculin surveys The combined results of surveys in Vredendal, Vredenburg-Saldanha and Swartland Schools are shown in Table 3. Using these data on the age-specific prevalence of infection the overall infection rate was calculated as approximately 2.5% per annum with no downward trend. Using the formula from Styb10,12 viz R = 1 - (1 Table 3. Tuberculin test results in school children without BCG scars in three communities in the Western Cape Health Region, South Africa, 1988 Age group 5-9 years f 8
IO-14 years f
3 6 8 IO 12 14 16 I8 20 22 >=24
178 0 0 7 9 IO 9 13 9 4 2 0 0
73.9 0.0 0.0 2.9 3.7 4.1 3.7 5.4 3.7 1.7 0.8 0.0 0.0
129 0 0 7 I8 17 28 29 30 I7 5 4 0
45.4 0.0 0.0 2.5 6.3 6.0 9.9 10.2 10.6 6.0 I.8 I.4 0.0
All
241
100.0
284
100.0
Induration (mm)
0 ,
7.9 Mean age Prevalence of infection* 17.8 13.01 - 22.67 95CI Risk of Infection’ 2.44% *Prevalence = (2f.>mode + f. mode)/n ‘Styblo’”
%
12.3 28.9 23.60 - 34.14 2.54%
TB and TBM
353
P) 1’a,to calculate the prevalence p at average age a years and the annual risk of infection at 2.5% per annum, the average prevalence of infected individuals was estimated to be 4.9% in the &4 year age group (age midpoint 2.5) and 21.4% in the 5-14 year age group (age midpoint 9.5). The average number of notified cases of all forms of TB per year in Coloured children in the WCHR during 1985- 1987 numbered 1607 in the O-4 year age group and 805 in the 5-14 year age group. The average number of cases of TBM found by active surveillance for the same population group, area and period numbered 46 in the O-4 year age group and 9 in the 5-14 year age group. This, together with census-derived population figures, allows estimation of the risk of tuberculous disease in Coloured children infected with Mycobacterium tuberculosis (Fig. 2). Of infected children in the O-4 year age group, 15.7% will develop clinical disease and 0.5% TBM. In the 5-14 year age group the risks of clinical disease and TBM among infected children diminish greatly (0.9% and 0.0 1% respectively).
DISCUSSION Over many years epidemiologists have noted that tuberculosis in children mirrors the severity and stage of the epidemic. I4 The TB epidemic is in the developmental or peak phase when children form a major proportion of the group affected by the disease. This can be seen in the WCHR where, compared to the rest of the country, there are higher rates of TBM in children, especially high TB notification rates among young adults (15-35 years), and higher risks of infection.” In the areas tested there was an annual risk of infection in excess of 2.0% - up to 3 times that found in most other areas of South Africa.16 This study has demonstrated high incidence rates of childhood TBM in the WCHR. Although the rates remain high even when all the population groups are grouped together as the denominator, TBM is only a significant problem in the Black and Coloured population groups of WCHR. This reflects the poorer socioeconomic conditions of many in these groups. The incidence rates of the disease are very low in the White and Asian groups, and are comparable to rates in developed countries. Since Blacks and Coloureds make up more than 80% of the total population of South Africa, the seriousness of the tuberculosis burden largely also gets reflected in the tremendous human need in the country. We compared our TBM rates with recent studies in other countries. There were, however, few references in the literature to incidence rates of TBM in children which would enable epidemiological comparisons to be drawn. Most of the available rates were from countries in which the rates were less than 1 per 100 000. Table 4 shows the rates (per 100 000) that were available, either directly from publications or indirectly from calculations on the information supplied therein.
354
Tubercle and Lung Disease
Prevalence of infection = 4.9% (n= 10258)
TB cases* = 1607
TBM cases+ = 46
infection = 21.4% (n = 86 752)
TB cases* = 805
TBM cases+ =9
Fig. 2 - A model of the annual risk of tuberculous disease in coloured children under 15 years of age infected with Mycobacterium tuberculosis, based on active surveillance of TBM and tuberculin surveys in the WCHR, 1985-1987. *TB cases (all forms) notified. +TBM cases via active surveillance.
As can be seen, the TBM rates in children in the WCHR are higher than any recent documented rates. However, direct comparison is not really possible, as these references are national estimates from passive reporting systems and are not really comparable with our study, which was an active surveillance system. Also, when considering international comparisons, one should be aware of the correlation between availability and validity of reported tuberculosis statistics and national wealth. International statistics are likely to be weakest in the areas where the tuberculosis situation is worst.17 Another contributory factor to weak statistics is the passive surveillance system of obtaining notifications. This system is fraught with problems which appear to be common to both developing and developed countries. A considerable under-notification of TBM cases occurred in our study. A report from England and Wales detailed the ambiguities and inaccuracies that a notification system can pose.*’ Data from the USA showed that 37% of TB cases were not reported in Washington, DC.2’ A study from Edinburgh showed that almost 40% of TB Table 4. years
International
comparison
of TBM rates in children aged o-4
Country
Period
Rate (per 100 000)
Columbia” Paraguay’* Argentinfsi8 Uruguay Nicarafta’* France Venezuela” Cubal South Africa” (national notifications) WCHR” (national notifications) WCHR (present study)
1984 1982 1984 1984 1982 1980-1984 1982 1980
2.4 1.3 0.6 0.37 0.31 0 0.11 0.0
1985-1987
5.41
1985-1987 1985-1987
14.67 24.3
cases were not reported.22 It appears that regular reappraisal of the notification system is necessary. Furthermore, communication with and involvement of the personnel who are doing the notifying may greatly improve the quality of the data. Of the TBM cases, nearly 80% were seen to be younger than 5 years of age. This is of importance as it is well recognized that the outcome of TBM is more severe in very young children. Rates from the rural areas were higher than those of the metropolitan area of greater Cape Town. This is likely due to less readily available primary health care facilities in these areas, and consequently higher risks of infection. Preventive measures should particularly be directed against young children under 2 years of age. In those living in the rural areas where the stage of presentation is often late, early diagnosis of meningitis (through good education of health professionals) needs to be improved in order to prevent deaths and sequelae. The late stage at which many present reflects deficiencies in primary health care delivery. In terms of chronic disability they ultimately present a massive burden to the hospital service and to the community. Accurate ascertainment of all cases of TBM is a valuable index of the total extent of tuberculosis disease in a region and is to be encouraged in areas of high TB prevalence. Coupled with regular tuberculin surveys on school entrants before administration of BCG vaccination, active surveillance of TBM provides an epidemiological procedure with a better and more consistent predictive value than do notifications of all forms of TB in children.
Acknowledgements We thank the Directorate of Epidemiology of the Department of National Health and Population Development in Pretoria for the data on notifications. We also wish to thank all the many health professionals who gave us access to their records and Ray Stroud of the Cape Town City Council for the data provided on population figures.
Childhood
References 1. Styblo K. Overview and epidemiologic assessment of the current global tuberculosis situation with an emphasis on control in deveioping countries. Rev Infect Dis 1989; 1 l(suppl2): 339-346. Scholtz WC. The South African climate. London: Cassell 1897: 12-174. Kiistner HGV. Tuberculosis notifications: an up-date. S Afr .I Sci 1986; 82: 386-387. Department of National Health and Population Development South Africa. Unpublished information. Department of National Health and Population Development South Africa. The Tuberculosis Control Programme. Epidemiol Comments 1987: 14: l&40. 6. Coetzee JN. An epidemiological investigation of tuberculous meningitis in the Western Province of the Cape of Good Hope. S Afr Med J 1953: 27: 441-446. 7. Coetzee JN. A bacteriological investigation of tuberculous meningitis in the Western Province of the Cape of Good Hope. Thesis presented in part futfilment of the requirements for the degree of Doctor of Medicine in the Department of Pathology, University of Cape Town, 1952. 8. Deeny JE, Walker MJ, Kibel MA et al. Tuberculous meningitis children in the Western Cape. Epidemiology and outcome. S Afr Med J 1985; 68: 75-78. 9. Kibel MA, Arens L, Deeny J et al. Tuberculous meningitis in the Western Cape from 1979-I 984: epidemiology and outcome. S Afr J Sci 1986; 82: 387-388. 10. Arens LJ, Deeny JE, Molten0 CD et al. Tuberculous meningitis in children in the Western Cape: neurological sequelae. Paediatr Rev Commun 1987; 1: 257-275.
TB and TBM
35.5
11. Styblo K. Surveillance of tuberculosis. Int J Epidemiol 1976: 5: 63-68. 12. Styblo K, Meijer J, Sutherland I. TSRU report no. I. The transmission of tubercle bacilli. Its trend in a human population. Bull Int Union Tuberc 1969; 42: 5-l 04. 13. Fourie PB. The prevalence and annual rate ot tuberculous infection in South Africa. Tubercle. 1983; 64: 1X1-192. 14. Styblo K. Recent advances in epidemiological research in tuberculosis. Adv Tuberc Res 1980; 20: l-63. 15. Department of National Health and Population Development South Africa. Extra-pulmonary tuberculosis. Epidemiol Comments 1987; 14: I-20. 16. Weyer K, Fourie PB. Die epidemiologie van tuberkulose in Suider-Afrika. South African Journal of Continuing Medical Education. 1989; 7: 239-247. 17. Comstock GW. Epidemiology of tuberculosis. Am Rev Respir Dis 1982; 125: 8-15. Koch Centennial Supplement. 18. World Health Organization. Tuberculosis en las Americas. WHO Collaborating Centre for the Epidemiology of Tubreculosis. Emilio Conti, Santa F& Argentina. Document PNSP/87-I I, 1987. 19. Lotte A, Burghard G. Petitjean R et al. Reduction in the risk of tuberculous meningitis in children in France. Impact of BCG vaccination. Bull Int Union Tuberc Lung Dis 1988; 63: 52-56. 20. Davies PDO, Darbyshire J, Nunn AJ et al. Ambiguities and inaccuracies in the notification system for tuberculosis in England and Wales. Community Med 1981; 3: 108-I 18. 21. Marier R. The reporting of communicable disease. Am J Epidemiol 1977; 105: 587-590. 22. Bradley BL, Kerr KM, Leitch AG et al. Notification of tuberculosis: can the pathologist help? B M J 1988: 297: 595.
S U M M A R Y. In recent years higher incidence rates of tuberculosis (TB) have been reported from the Western Cape than from other health regions of South Africa. In contrast to the various pulmonary forms of tuberculosis, tuberculous meningitis (TBM) always requires hospital admission, and can thus be used as an indicator of the extent of the infection in a community, as well as providing a measure of the effectiveness of primary and secondary preventive measures. In the present study an attempt was made to identify all cases of tuberculous meningitis aged 14 years and younger which occurred in the region, by checking notifications and the records of all hospitals, and verifying diagnosis against set criteria. Rates for the entire period were calculated according to updated census data. There was a total of 689 confirmed cases, of which only 55% had been notified. Of the 238 cases confirmed in the 3-years period, 1985-1987,25.2% were under 1 year, 51.7% under 2 years, and 79.8% under 5 years of age. Age-specific incidence per 100 000 children were respectively 31.5 (O-l years), 17.1 (l-4 years), 4.8 (5-9 years), and 0.7 (10-14 years). Rates in rural areas were far higher than in metropolitan regions. Utilizing tuberculin test data and total notifications, the following risks could be calculated for ‘Coloured’ children (of mixed race) aged o-4 years: 2-3% annual risk of infection; 15.7% risk of TB in infected population; 0.5% risk of TBM in infected population; 0.9% risk of TB in children aged 5-14 years; 0.01% risk of TBM in children aged 5-14 years.
k . Dans les an&es recentes les taux d’incidence de la tuberculose signales au Cap Ouest ont et6 plus &eves que ceux signal& dans les autres regions sanitaires d’Afrique du Sud. A l’inverse des differentes formes pulmonaires de la tuberculose (TB), la meningite tuberculeuse (TBM) necessite toujours une admission a l’hopital, et peut done &treutilisee comme un indicateur de l’etendue de l’infection dans une communaute, en m$me temps qu’elle fournit une mesure de l’efficacite des mesures de prevention primaire et secondaire. Au tours de la presente etude on a tent& d’identifier tous les cas de meningite tuberculeuse apparus dans la region chez des sujets LgCsde 14 ans et moins, en examinant les notifications et les registres de tous les h8pitaux et en verifiant les diagnostics par rapport a des criteres prC-Ctablis.Les taux pour l’ensemble de la periode ont CtC calcules a partir des chiffres mis a jour du recensement. 11y avait un total de 689 cas confirmCs dont seulement 55% avaient Cte notifies. Sur le total des cas, 25,2% Ctaient lges de moins d’un an, 51,7% de moins de 2 ans et 79,8% de moins de 5 ans. L’incidence selon l’age, pour 100 000 enfants, Ctait de 31,5 (0 a 1 an), 17,l (2 a 4 ans), 4,8 (5 a 9 ans) et 0,7 (10 a 14 ans). Les taux provenant des regions rurales Ctaient bien plus Cleves que ceux de la region metropolitaine. En utilisant les donnees du test tuberculinique et le total des notifications, les risques suivants ont pu Ctre calcules pour les enfants ‘m&is (de race mixte) LgCsde 0 a 4 ans: risque annuel d’infection de 2 a 3% ; risque de tuberculose dans une population infectbe, 15,6% ; risque de TBM dans une population infectee, 0,5% ; risque de TB chez des enfants LgCsde 5 a 14 ans, 0,9% ; risque de TBM chez des enfants Igb de 5 a 14 ans, 0,Ol %.
R k S UM
R ES U M E N . En 10s ultimos adios las tasas de incidencia de tuberculosis informadas por Western Cape han sido miis elevadas que en otras regiones de Africa de1 Sur. Contrariamente a las diversas formas de tuberculosis pulmonar (TB), la meningitis tuberculosa (MTB) requiere siempre una hospitalizaci6n y de esta manera puede
Correspondence to: Professor M. A. Kibel, Department of Paediatrics and Child Health, Child Health Unit, Children’s Centre, 46 Sawkins Road, Rondebosch 7700, South Africa. 349
350
Tubercle and Lung Disease
ser utilizada coma un indicador de la extensi6n de la infection en la comunidad y para medir la eficacia de las actividades de prevenci6n primaria y secundaria. En el presente estudio se intent6 identiflcar todos 10s cases de MTB en nifios de 14 adios de edad o menos detectados en la region, revisando las declaraciones y 10s registros de todos 10s hospitales y verificando el diagn6stico con respect0 a criterios preestahlecidos. Las tasas para el period0 complete fueron calculadas utilizando datos actualizados de1 censo. Se encontro un total de 689 cases confirmados, de 10s cuales ~610el55 % habia sido declarado. Del total de cases, el25,2 % tenia menos de 1 auo de edad, el51,7 % menos de 2 adios y el79,8 % menos de 5 adios. La incidencia especifica por grupos de edad por 100 000 niiios era: 31,5 (O-l aiio), 17,l (2-4 adios), 4,8 (5-9 adios) y 0,7 (10-14 adios). Las tasas en las regiones rurales eran mucho mis elevadas que en las regiones metropolitanas. Utilizando 10s datos de la prueba tuberculinica y el total de declaraciones, se pudo calcular un cierto numero de riesgos para 10s nifios ‘mestizos’ (de raza mixta). Para 10s niiios de e4 adios: 2-3 % de riesgo de infecci6n anual, 15,6 % de riesgo de TB en la problaci6n infectada, 0,5 % de riesgo de MTB en la problacion infectada; para 10s nifios de 5-14 adios: 0,9 % de riesgo de TB; para 10s niiios de 5-14 adios: 0,Ol % de riesgo de MTB.
INTRODUCTION Worldwide interest in tuberculosis (TB) has been reawakened by the epidemic of acquired immunodeficiency syndrome (AIDS) which is currently threatening the global tuberculosis situation. This is especially relevant in developing countries where there is a high prevalence of infection with Mycobacterium tuberculosis, such as in Africa.’ In South Africa, TB has been a problem only since the 19th century when immigrants, many of whom were seeking a favourable climate to recover from consumption, arrived from various parts of Europe.’ Notification of TB was started in 1922. A gradual increase in reported incidence was then noted, which reached an alltime high in the mid-1960s with a rate around 350/100 000 of the general population. By 1986 the incidence rate had declined to around 200/100 000,3 and has remained at this level since (237/100 000 in 1990).4 There has, however, been an increase in tuberculosis notifications from the Western Cape Health Region (WCHR): one of the three health regions in the Cape Province. This region, with a total population of approximately 3 million in 1986, includes Cape Town and environs and has traditionally been inhabited by White people and people of mixed ethnic origin (so-called ‘Coloured’). In the last 20-30 years a major influx of rural Black families has taken place, particularly into the peri-urban areas of Cape Town. They have carried with them the experience of high TB prevalence from their place of origin. In 1986, for example, the respective total TB incidence rates for Coloured and Black populations were 628 and 976 per 100 000 in the WCHR, compared with an average of 280 and 315 per 100 000 for the rest of the country.5 Differences in case-finding and reporting practices may partially explain this discrepancy, but would be unlikely to result in rates approximately 3 times higher than elsewhere. Tuberculous meningitis (TBM) has long been recognized as a problem in the WCHR. In 1950 an epidemiological study on TBM was carried out in what was then known as the Western Province of the Cape of Good Hope.6,7 This showed 163 cases of TBM originating
from the Cape Peninsula and 37 cases from various towns in the rest of the area over a 13-month period. Using these counts and population denominator figures derived from census data available for the time period, an incidence rate of 98 per 100 000 population was calculated for Coloured children below the age of 15 years residing in the metropolitan area of Cape Town. Further studies for the period 1979-1984 revealed that, whereas rates had dropped far below this figure, TBM was still a significant problem in the region.8,9x’0 Mortality was 24%,8 and there was a high occurrence of cerebral palsy (53%) and mental retardation (46%) among the survivors.” In an attempt to better understand the TB situation in the WCHR, we have looked at TB in childhood, as the annual infection and case rates of childhood TB, especially TBM, have significance as markers of the size of the infectious pool in the community.” The annual risk of infection, based on the estimated prevalence of infection according to skin test responses following tuberculin testing in young children, has been shown to be a useful indicator of the TB situation.” This relationship has been translated into an index referred to as the annual rate or risk of infection,” and has also been applied to children in most areas of Southern Africa, including the Western Cape.13 TBM, the most serious complication of childhood TB, is a relatively easily verifiable condition, as it always requires hospital admission and laboratory confirmation. As spontaneous recovery from TBM is virtually impossible without treatment, it provides a useful indicator of the extent of TB in the community, especially in areas of high tuberculosis prevalence.” Styblo has suggested that 1 case of TBM can be equated to 12 cases of smear-positive TB in the community.” The aims of the present study were three-fold: firstly, to determine the incidence of TBM over the period 1985-1987 in order to draw comparisons with previous studies; secondly, to assess the completeness of the registration system of TBM notifications; thirdly, to develop a model to predict risks of TBM in children infected with TB based on tuberculin skin test responses and total notifications. By estimating the proportion of infected children in a particular age group by tuberculin testing,
ChildhoodTB and TBM 35 I and combining this information with notification data from the same target population, the risk of TBM developing in this age group can be more accurately determined.
Incidence rates Rates for the entire period (1979-1987) culated according to updated census data.*
were recal-
Tuberculin skin test reactions and risk of infection PATIENTS AND METHODS Tuberculous meningitis Case jinding Information on all cases of TBM occurring within the WCHR over a 3-year period (1985-1987) was identified and pooled with data previously obtained for the years 1979- 1984.“,9 This entailed examining notifications records from the Department of National Health and Population Development. In addition all 75 hospitals in the area were canvassed for cases of TBM and folders were examined wherever possible. This allowed for checking of notification source data (by name, notifying authority, date, etc.) to determine the degree of under/over-reporting. Patients were regarded as resident in the WCHR if they had been living permanently within the defined area or had lived there for 6 months before illness; or if they had previously been resident in the area and had been referred for health care. Only children aged 14 years or younger at the time of diagnosis and diagnosed as having TBM between 1 January 1985 and 3 1 December 1987 were included. Time of diagnosis was taken as the time when treatment was started. Case dejinition Criteria for the establishment of a diagnosis of TBM were the same as for the previous two studiess.Y and required either: 1. Three or more of the following: (a) CSF pleocytosis and protein > 0.6g/l; (b) Evidence of TB, such as chest radiographic appearances, or sputum or gastric washings positive for Mycobacterium tuberculosis on culture, or a positive tuberculin skin test; (c) CSF culture-positive, or bromide partition ratio < 1.6 or CSF adenosine deaminate activity (ADA) > 5~0; (d) Clinical course consistent with TBM, or 2. Autopsy findings indicating TBM. Culture-positive cases (CSF or gastric washings) formed only a minority in our series. The above-mentioned case definition was the best we could come up with in an epidemiological study such as this, where cases were managed in a large number of hospitals. We thus required (I) at least 3 out of 4 of the following: (a) typical CSF, (b) evidence of TB elsewhere, (c) more specific CSF evidence and (d) clinical cause which in retrospect fitted the picture of TBM; or (2) autopsy evidence of TBM.
Tuberculin surveys in school children aged 5-14 years were carried out in Vredendal, Vredenburg/Saldanha and Swartland, all rural areas within the WCHR which have reported high TB rates. Mantoux testing was performed with 2 TU of Danish RT23 PPD containing Tween 80. Tests were read after 72 h with indurations measured transversely to the long axis of the forearm. In South Africa, BCG vaccination is given percutaneously by multiple puncture at birth, at school entry and at school leaving. Studies by Fourie & Kibel (unpublished) have shown that revaccination at school entry tends to produce significant tuberculin reactions lasting several years, sometimes without visible scarring. As much as 11% of Mantoux reactions measuring 10 mm or more in revaccinated children can be ascribed to BCG vaccination and not to natural infection. In our study, BCG scars were noted in 86% of children, and consequently, in order to limit as far as possible overestimation of natural infection prevalence because of BCGrelated reactions, calculations were based only on indurations from children without visible BCG scars. Prevalence of infection was calculated not on the basis of a cut-off point above which indurations were regarded as positive, but on the location of the mode of the frequency distribution. Measurable indurations tend to be approximately normally distributed in high TB prevalence communities. By adding twice the proportion of indurations measuring greater than the mode of the proportions of indurations at the mode, a better estimate is obtained than would be the case if the usual ‘greater or equal to 10 mm’ cut-off point is utilized. The expression employed was: (2 f.>mode + f. mode)/n where f. mode = frequency of indurations senting the mode f.>mode = frequency of indurations than the mode = number of observations n
repregreater
Total notifications of childhood tuberculosis Notifications of all forms of tuberculosis (ICD 010-018) in respect of children under 15 years of age from WCHR were obtained from the Department of National Health
*Baselinecensus data used came from the 1980and 1985 Central Statistical Services Population Census. (Reports Number 02-80-04 and 02-85-02). These needed to be adjusted due to under-enumeration. However, it is accepted that the Black population figures represent an undercount and. therefore, use was made of the projections of the population as set out by the Cape Town Metropolitan Transport Area of the City of Cape Town to determine a second population denominator.
352
Tubercle and Lung Disease
and Population 1985-1987.
Development
for
the
3-year
period
Table 1. Total numbers of cases of TBM by population WCHR, 1979-1987 Population
RESULTS Active surveillance of tuberculous meningitis Total numbers of cases of TBM in the WCHR for the entire period 1979-1987 in children under 15 years of age are shown in Table 1. The mean annual incidence rate per 100 000 children for the period 1985-1987 in Coloured children under 15 years of age was 9.0. The mean annual incidence rate for the same period and age group in Black children was 17.1, but after adjusting for population under-enumeration and excluding those cases intermittently resident outside of the study region, the incidence was 10.0. Figure 1 shows the age specific incidence of TBM in children for the whole of the WCHR (total population in age group as denominator, being based on census date) for the years 1985-1987. Most of the cases occurred in children under the age of 5 years (25.2% under 1 year; 51.7% under 2 years and 79.8% under 5 years). For the period 1985-1987, 68% of the cases were male and 32% female. For the same period there appeared to be no significant seasonal variation in numbers. Ongoing large-scale migration of the Black population in and out of the WCHR in recent years has resulted in a lack of the necessary demographic information required to conduct finer analysis of disease rates than those presented above. Furthermore, it is evident that TBM is
40
group
1982-1984(9)
1985-1987
Coloured Black White Asian
125 59 1 0
190 75 1 0
166 72 0 0
Total
185
266
238
not a significant problem among Whites and Asians. We have, therefore, restricted further analysis of incidence rates to the Coloured population only. Table 2 shows a comparison of the TBM incidence rates in the Coloured population (for the age group O-4 years) between the urban and peri-urban areas of Cape town and the rest of the WCHR, which consists largely of rural areas and small towns, These rates were obtained by dividing the average annual number of cases for each 3-year period with the average population denominator for that period. It will be seen that the rates for greater Cape Town are approximately half those of the rest of the region. The higher incidence in the predominantly rural areas is also demonstrated in the O-14 year age group. The mean annual TBM incidence rate per 100 000 Coloured children in the O-14 year age group for the entire period 1979-1987 is 5.9 for greater Cape Town compared to 10.8 for the rest of the WCHR. The mean ratio of TBM to all forms of TB in Coloured children under the age of 5 years, calculated over the same period (1979-1987), is also higher in the rest of the WCHR (7.0%) as compared to greater Cape Town (2.3%).
lncldenoe per 100 000
4.8
S-Q l-4 Age Groups (years) Fig. l-
1979-1981(8)
group in the
Age -specific incidence rates of TBM in children, WCHR, 1985-1987.
Childhood Table 2. according
TBM incidence rates in Coloured children aged O-4 years to region
1979-1981 1982-1984 19X5-1987
Notijcation
Region of greater Cape Town (per 100 000)
Rest of Western Cape Health Region (per 100 000)
12.0
21.3 30.9 29.0
18.9 13.6
of TBM
Of the TBM cases notijed during the period 1985-1987, 16% were excluded because of an incorrect diagnosis, a double notification or a clerical error. The remaining notified TBM cases formed 56% of the total number of TBM cases that had been verified for the period 1985-1987. While there was thus an under-reporting of 44%, the true error in under-reporting was less as the incorrect notifications would have been included in the notification statistics of the Department of National Health and Population Development. Of note is that of the 44% of cases that were not in the records of notifications, 15% were thought to have been notified according to medical records examined or doctors questioned. Of the 23 children notified as deaths, only 2 had been notified as cases while alive. Tuberculin surveys The combined results of surveys in Vredendal, Vredenburg-Saldanha and Swartland Schools are shown in Table 3. Using these data on the age-specific prevalence of infection the overall infection rate was calculated as approximately 2.5% per annum with no downward trend. Using the formula from Styb10,12 viz R = 1 - (1 Table 3. Tuberculin test results in school children without BCG scars in three communities in the Western Cape Health Region, South Africa, 1988 Age group 5-9 years f 8
IO-14 years f
3 6 8 IO 12 14 16 I8 20 22 >=24
178 0 0 7 9 IO 9 13 9 4 2 0 0
73.9 0.0 0.0 2.9 3.7 4.1 3.7 5.4 3.7 1.7 0.8 0.0 0.0
129 0 0 7 I8 17 28 29 30 I7 5 4 0
45.4 0.0 0.0 2.5 6.3 6.0 9.9 10.2 10.6 6.0 I.8 I.4 0.0
All
241
100.0
284
100.0
Induration (mm)
0 ,
7.9 Mean age Prevalence of infection* 17.8 13.01 - 22.67 95CI Risk of Infection’ 2.44% *Prevalence = (2f.>mode + f. mode)/n ‘Styblo’”
%
12.3 28.9 23.60 - 34.14 2.54%
TB and TBM
353
P) 1’a,to calculate the prevalence p at average age a years and the annual risk of infection at 2.5% per annum, the average prevalence of infected individuals was estimated to be 4.9% in the &4 year age group (age midpoint 2.5) and 21.4% in the 5-14 year age group (age midpoint 9.5). The average number of notified cases of all forms of TB per year in Coloured children in the WCHR during 1985- 1987 numbered 1607 in the O-4 year age group and 805 in the 5-14 year age group. The average number of cases of TBM found by active surveillance for the same population group, area and period numbered 46 in the O-4 year age group and 9 in the 5-14 year age group. This, together with census-derived population figures, allows estimation of the risk of tuberculous disease in Coloured children infected with Mycobacterium tuberculosis (Fig. 2). Of infected children in the O-4 year age group, 15.7% will develop clinical disease and 0.5% TBM. In the 5-14 year age group the risks of clinical disease and TBM among infected children diminish greatly (0.9% and 0.0 1% respectively).
DISCUSSION Over many years epidemiologists have noted that tuberculosis in children mirrors the severity and stage of the epidemic. I4 The TB epidemic is in the developmental or peak phase when children form a major proportion of the group affected by the disease. This can be seen in the WCHR where, compared to the rest of the country, there are higher rates of TBM in children, especially high TB notification rates among young adults (15-35 years), and higher risks of infection.” In the areas tested there was an annual risk of infection in excess of 2.0% - up to 3 times that found in most other areas of South Africa.16 This study has demonstrated high incidence rates of childhood TBM in the WCHR. Although the rates remain high even when all the population groups are grouped together as the denominator, TBM is only a significant problem in the Black and Coloured population groups of WCHR. This reflects the poorer socioeconomic conditions of many in these groups. The incidence rates of the disease are very low in the White and Asian groups, and are comparable to rates in developed countries. Since Blacks and Coloureds make up more than 80% of the total population of South Africa, the seriousness of the tuberculosis burden largely also gets reflected in the tremendous human need in the country. We compared our TBM rates with recent studies in other countries. There were, however, few references in the literature to incidence rates of TBM in children which would enable epidemiological comparisons to be drawn. Most of the available rates were from countries in which the rates were less than 1 per 100 000. Table 4 shows the rates (per 100 000) that were available, either directly from publications or indirectly from calculations on the information supplied therein.
354
Tubercle and Lung Disease
Prevalence of infection = 4.9% (n= 10258)
TB cases* = 1607
TBM cases+ = 46
infection = 21.4% (n = 86 752)
TB cases* = 805
TBM cases+ =9
Fig. 2 - A model of the annual risk of tuberculous disease in coloured children under 15 years of age infected with Mycobacterium tuberculosis, based on active surveillance of TBM and tuberculin surveys in the WCHR, 1985-1987. *TB cases (all forms) notified. +TBM cases via active surveillance.
As can be seen, the TBM rates in children in the WCHR are higher than any recent documented rates. However, direct comparison is not really possible, as these references are national estimates from passive reporting systems and are not really comparable with our study, which was an active surveillance system. Also, when considering international comparisons, one should be aware of the correlation between availability and validity of reported tuberculosis statistics and national wealth. International statistics are likely to be weakest in the areas where the tuberculosis situation is worst.17 Another contributory factor to weak statistics is the passive surveillance system of obtaining notifications. This system is fraught with problems which appear to be common to both developing and developed countries. A considerable under-notification of TBM cases occurred in our study. A report from England and Wales detailed the ambiguities and inaccuracies that a notification system can pose.*’ Data from the USA showed that 37% of TB cases were not reported in Washington, DC.2’ A study from Edinburgh showed that almost 40% of TB Table 4. years
International
comparison
of TBM rates in children aged o-4
Country
Period
Rate (per 100 000)
Columbia” Paraguay’* Argentinfsi8 Uruguay Nicarafta’* France Venezuela” Cubal South Africa” (national notifications) WCHR” (national notifications) WCHR (present study)
1984 1982 1984 1984 1982 1980-1984 1982 1980
2.4 1.3 0.6 0.37 0.31 0 0.11 0.0
1985-1987
5.41
1985-1987 1985-1987
14.67 24.3
cases were not reported.22 It appears that regular reappraisal of the notification system is necessary. Furthermore, communication with and involvement of the personnel who are doing the notifying may greatly improve the quality of the data. Of the TBM cases, nearly 80% were seen to be younger than 5 years of age. This is of importance as it is well recognized that the outcome of TBM is more severe in very young children. Rates from the rural areas were higher than those of the metropolitan area of greater Cape Town. This is likely due to less readily available primary health care facilities in these areas, and consequently higher risks of infection. Preventive measures should particularly be directed against young children under 2 years of age. In those living in the rural areas where the stage of presentation is often late, early diagnosis of meningitis (through good education of health professionals) needs to be improved in order to prevent deaths and sequelae. The late stage at which many present reflects deficiencies in primary health care delivery. In terms of chronic disability they ultimately present a massive burden to the hospital service and to the community. Accurate ascertainment of all cases of TBM is a valuable index of the total extent of tuberculosis disease in a region and is to be encouraged in areas of high TB prevalence. Coupled with regular tuberculin surveys on school entrants before administration of BCG vaccination, active surveillance of TBM provides an epidemiological procedure with a better and more consistent predictive value than do notifications of all forms of TB in children.
Acknowledgements We thank the Directorate of Epidemiology of the Department of National Health and Population Development in Pretoria for the data on notifications. We also wish to thank all the many health professionals who gave us access to their records and Ray Stroud of the Cape Town City Council for the data provided on population figures.
Childhood
References 1. Styblo K. Overview and epidemiologic assessment of the current global tuberculosis situation with an emphasis on control in deveioping countries. Rev Infect Dis 1989; 1 l(suppl2): 339-346. Scholtz WC. The South African climate. London: Cassell 1897: 12-174. Kiistner HGV. Tuberculosis notifications: an up-date. S Afr .I Sci 1986; 82: 386-387. Department of National Health and Population Development South Africa. Unpublished information. Department of National Health and Population Development South Africa. The Tuberculosis Control Programme. Epidemiol Comments 1987: 14: l&40. 6. Coetzee JN. An epidemiological investigation of tuberculous meningitis in the Western Province of the Cape of Good Hope. S Afr Med J 1953: 27: 441-446. 7. Coetzee JN. A bacteriological investigation of tuberculous meningitis in the Western Province of the Cape of Good Hope. Thesis presented in part futfilment of the requirements for the degree of Doctor of Medicine in the Department of Pathology, University of Cape Town, 1952. 8. Deeny JE, Walker MJ, Kibel MA et al. Tuberculous meningitis children in the Western Cape. Epidemiology and outcome. S Afr Med J 1985; 68: 75-78. 9. Kibel MA, Arens L, Deeny J et al. Tuberculous meningitis in the Western Cape from 1979-I 984: epidemiology and outcome. S Afr J Sci 1986; 82: 387-388. 10. Arens LJ, Deeny JE, Molten0 CD et al. Tuberculous meningitis in children in the Western Cape: neurological sequelae. Paediatr Rev Commun 1987; 1: 257-275.
TB and TBM
35.5
11. Styblo K. Surveillance of tuberculosis. Int J Epidemiol 1976: 5: 63-68. 12. Styblo K, Meijer J, Sutherland I. TSRU report no. I. The transmission of tubercle bacilli. Its trend in a human population. Bull Int Union Tuberc 1969; 42: 5-l 04. 13. Fourie PB. The prevalence and annual rate ot tuberculous infection in South Africa. Tubercle. 1983; 64: 1X1-192. 14. Styblo K. Recent advances in epidemiological research in tuberculosis. Adv Tuberc Res 1980; 20: l-63. 15. Department of National Health and Population Development South Africa. Extra-pulmonary tuberculosis. Epidemiol Comments 1987; 14: I-20. 16. Weyer K, Fourie PB. Die epidemiologie van tuberkulose in Suider-Afrika. South African Journal of Continuing Medical Education. 1989; 7: 239-247. 17. Comstock GW. Epidemiology of tuberculosis. Am Rev Respir Dis 1982; 125: 8-15. Koch Centennial Supplement. 18. World Health Organization. Tuberculosis en las Americas. WHO Collaborating Centre for the Epidemiology of Tubreculosis. Emilio Conti, Santa F& Argentina. Document PNSP/87-I I, 1987. 19. Lotte A, Burghard G. Petitjean R et al. Reduction in the risk of tuberculous meningitis in children in France. Impact of BCG vaccination. Bull Int Union Tuberc Lung Dis 1988; 63: 52-56. 20. Davies PDO, Darbyshire J, Nunn AJ et al. Ambiguities and inaccuracies in the notification system for tuberculosis in England and Wales. Community Med 1981; 3: 108-I 18. 21. Marier R. The reporting of communicable disease. Am J Epidemiol 1977; 105: 587-590. 22. Bradley BL, Kerr KM, Leitch AG et al. Notification of tuberculosis: can the pathologist help? B M J 1988: 297: 595.
