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Geographic variations in the prevalence of sensitivity to PPD-S and PPD-B in Western Australia
Tubercle, Lond., (1967). 48. 273
G E O G R A P H I C V A R I A T I O N S IN T H E P R E V A L E N C E O F S E N S I T I V I T Y T O P P D - S AND P P D - B IN W E S T E R N A U S T R A L I A By J. T. SMVrlt* and R. M. PORTER fi'om Sir Charh's Gairdner Hospital and The (?hest Clinic, Perth. IVestern Australia
SUMMARY Between I960 and 1966 comparative Mantoux testing using PPD-S and PPD-B was performed on 11,885 school children living in different areas in Western Australia. PPD-B is prepared from Battey mycobacterfa and was diluted before delivetT to us to correspond in protein ~,nd nitrogen content with the PPD-S. The proportion of" school children giving a larger reaction to each antigen increased with age: and boys gave a slightly kigher proportion of larger reactions to both antigens. Geographic variation was seen in two ways. A larger reaction to PPD-S was given by 10% of children not born in Australia and by only 3.I ~ of Australian-born children. This accords with the known higher incidence of pulmonary tuberculosis in migrants to this State. A larger reaction to PPD-B was given by less than 25 ~o of boys age 13-17 years in the southern part of the state and by over 500/,, of boys of the same age group in the northern and eastern parts, which in general have a lower rainfall and higher average temperature. The proportion of larger reactions to PPD-B was lower in Perth, the principal city of the state, than in surrounding agricultural areas. The proportion of childre~ giving a larger i'eaction to PPD-S.showed little geographic variation. In Weslern Australia most reactions under 10 ram. diameter to 5 TU of PPD-S are probably caused by sensitization by agents other than Mycobacterium tuberculosis.
R~SUM~Entre 1960 et 1966, 11.885 6coliers habitant dans difi~rentes r6gions de l'Australie de l'ouest ont 6t6 testds comparativement avec de la .PPD-S et de la PPD-B. Cette d.erni,~re est pr6parde ~ partir d'un bacille Battey et dilu6e avant usage afin que son contenu protdique et azot6 corresponde/l celui de la PPD-S. La proportion d'6coliers r,~agissant ~ l'un ou l'autre antigone augmentait avec l'fige et la proportion de ceux avec des r,~actions plus importa'ntes aux deux antig6nes 6talent 16g~rement sup6rieure chez les gar~;ons. Des variations g6ographiques ont 6t6 remarqu6es dans deux sens. t0% des enfants n6s en. dehors d'Australie r6agissaient plus fortement h la PPD-S, contre 3,1 ~ seulement parmi les Australiens de naissance. Ceci est en accord avec la plus grande incidence de tuberculose pulmonaire commr cnez les immigrants de ce pays. Une rdaction pr6pond6rante/l la PPD-B a 6t6 trouvde chez~moins de 25 % des garqons 5.g6s d e l 3 5.17 arts darts la pattie Nord de l'Etat, et chez plus de 5 0 ~ des gar~;ons du m~me groupe d'fige habitant dans la partie Nord-est, o~ en g6nfral les pluies sont moins abon* Present address: Hawkmoor Chest Hospital, BoveyTracey, Devon.
274
TU~vRCt, V. dantes et la tempfrature moyenne plus 61ev6e. La proportion de r6actions plus forles "h la PPD-B 6tait plus basse fi Perth, principale ville de l'Etat, que dans les r6gions agricoles avoisinantes. La proportion d'enfants reagissant plus ~t la PPD-S n'a montr6 que peu de variations g6ographiques. En Australie de l'Ouest, la plupart des r6actions au-desgous dr, !0 mm. de diam&re ~'~ 5 UT de PPD-S est probablement due ~ une sensibilisation par des organ;~:mes attires que
M. tuberculosis.
RESUMEN Entre 1960 y 1966 se efectuaron reacciones de Mantoux comparadas con PPD-S y PPD-B en I1.885 escolares que vivian en fireas Oiferentes de Australia Occidental. E! PPD-B se prepar6 con mycobacterias Battey y fur diluido antes de llegar a nuestro poder de tal modo que su contenido de proteinas y nitr6geno fuera anfilogo al del PPD-S. La proporci6n de escolares que di6 mayor reacci6n frenle a cada antigeno aument6 con la edad ; por su parte, los nifios varones dieron una discreta mayor proporci6n de reacciones intensas ambos antigenos. Hubo variaciones geogrtificas en ambos sentidos. Hubo una reacci6n mils intensa al PPD-S en el 10~ de los nifios no nacidos en Australia y era el 3'1 o(, de los nacidos eta Australia. Esto coincide con ia conodida mayor incidencia de tuberculosis pulmonar en los int~igrnntes. Hubo una intensa reacci6n al PPD-B en menos del 25~,, de los nifios de 13 a 17 afios en la regi6n sur del estado y e n mils del 50'~,,] de los nifios del mismo grupo etario de las regiones norte y este, regiones que generalmente tienen menor precipitaci6n pluvial y mayor temperatura promedio. La proporci6n de reacclones m~is intensas al PPD-B fu6 m~is baja en Perth, la ciudad principal del estado, que en las ~ireas agricolas circundantes. La proporci6n de nifios con intensa reacci6n al PPD-S mostr6 poca variaci6n geogrtifica. En Australia Occidental la mayoria de las reacciones por debajo de 10 mm. de dihmetro a 5 UT de PPD-S son probablement producidas por la sensibilizacifn a un agentc que no es el Mj,cobacterium tuberculosis.
Introduction In Western Australia about 1()~ of school children give a positive reaction to tuberculin on multiple puncture testing. In Queensland the reaction rate is higher and varies from place to place within the State, probably because of non-tuberculous sensitization (Abrahams and Silverstone, 1961). It seemed likely that non-tuberculous sensitization was present in Western Australia and we report a survey of the incidence of sensitization to PPD-S and PPD-B in school children in different parts of the State. Methods
Study Population School children in widely differing areas of the State were tested (Fig. 1). Through the Director of Tuberculosis Control the programme was integrated with a mass x-ray survey of the population and routine tuberculin testing of school children over the period 1960 to 1966. The age of children tested was from 5-17 years. Co-operation by the school staff, pupils and parents, was very good. 90-95 ,"/oof the total enrolment of each school was tested. Parents were informed of the nature o f the test and requested to give their consent and supply information concerning the country of birth of the child and previous BCG vaccination. Results from children who had had BCG were not included in the survey.
1Ui|t'~('12LtN
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AIltlgens were supplied by the U.S. Public H e a h h Service lhro,,i~h lhe courtesy o f D r . Lydia Edwatd~. p P D - S ( i n l e r n a l i o n a l staltdard h u m a n slrain purified protein deri~.ative, Sctberl arld G l e n n , 1941) ~ind P P D - B ",.',ere used. P P D - B is prepared from Batt,2y organisms and was dil u l e d before deliver', to w-. to cerrcspond in protein .and nilro~e,l content v, ith PPD-S ( A f f , o n t i , 1959)9 O n i h i , basis ('J-I n l l of antlgen c olres ponds to 5. T I J s l r e ~ g l h
1 1 1
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i
in 1he ~u:~e~ {Instt--LI~- Unlled IK ng~ o, on Ihe ~.n t ~1r
ch~m,cally cleaned b,efor~ us~ [):".po'~,xble 26 gauge llIlr~1-dernl.Jl n~.'cdles were t t ~ ' d Procedure ~t~iections of 0-I mL of each ~mh.cen were gi'.en into lhe flexor surface of each folear.n Almost all the injections were given by a ~"am of four ~lnd reac~iorls were read alter 72 hollrs by the same team. Induration wa~ measured transversely in millirrtelres using dividers and a ruler9 reactions which did not differ by more Ihan 2 ram. were regarded as equal9 Re~Its
Results were analyzed in terms of larger reaetio,ls to each antigen. Reaction ,~ize~wer~ also noted
TUBERCLE
276
TABLE I.--LARGER REACTIONSTO 5 T.U. OF PPD-B OR PPD-S IN DIFFERENTAGE GROUPS Age O'ears) Total 10--12 Total children
1,302
PPD-B > PPD-S PPD-S > PPD-B _._
i
13--17
i
2,651 (!00%) i 7,932 (100%) t. 729 "(27.5%) i 2,389 (30"2~ 56 (2"1%) i 344 (4"40/0)
(100%)
(23.2%) 25 (1.9%) _ 303
iI
I! ,885
.
i i
3.421 425
TABLE II.~I,,ARGER REAL-q'IONgTO 5 T.U. OF PPD-B ANn PPD-S IN BOYSAND GIRLS IN DIFFERENTAGE GROUPS Age groups ()'ears)
Total tested*
I PPD-B> PPD.s [ No.. ~f
PPD-S> PPD-B No. o//,f
[
[
5--9 (Boys) (Girls) 10~12 (Boys) (Girls)
i
13~!7 (.Boys) (Girls) Total
(Boys) (Girls)
.
656 646
i I
165 138
25.0 21 "0
14 I1
2.0 ! .7
1,405 1,246
i 1
405 324
28.2 26.0
33 23
2"3 1-9
4,136 3,786
] 1,514 i 870
36.2 22.7
200 142
4.9 3.7
6,197 5,678
i 2,084 ] 1,332
i
247 176
* Results from 10 children omitted--sex not recorded. "1"Based on the total t~sted in each group. and analyzed separately. Results of comparative testing of 11,885 children were analyzed. A larger reaction to PPD-B was given by 3,421 (28 ~ ) of these. A larger reaction to P P D - S was given by 425 (3.6 ~). Variation with Age The proportion of each age group giving a larger reaction to each antigen is shown in Table I. The proportion of school children giving a larger reaction to each antigen increases with. age. Relation to S e x Results of comparative testing in each age group were analyzed by sex. Results are shown in Table Ii. There is a slightly higher proportion of larger reactions to both antigens amongst boys. Geographic Variations Geographic variation was evident in two ways : - (I) Children not born in Australia showed a higher proportion of larger reactions to PPD-S than children born in Australia (Table l l l and Fig. 2). A larger reaction to PPD-S was given by I0-0 ~ of children not born in Australia and by only 3.1 ~o of Australian born children. The difference is significant. It is possible that some children born overseas had had B C G vaccination which was not recorded by their parents. This factor was unlikely to have influenced the results significantly. (2) Children living in the south of Western Australia had a lower proportion of larger reactions to PPD-B than those living elsewhere (Fig. 3). In Geraldton, Kalgoorlie and
TUBERCULIN SENSITIVITY
277
TABLE III.--COMPARATIVE SKIN TLSTING CttILDREN AGE 13--17 YEARS BORN IN AUSTRALIAAND NOT BORN IN AUSTRALIA Australian horn
Not Australian born
Total children*
6,449 (I00%}
PPD-B>PPD-S
2,064 (32.1~
314 (22"4%)
PPD-S>PPD-B
202 (3"1%)
140 (10"0".~1
!,400
(100~,~)
* Results from 83 children omitted--country of birth not recorded. Derby over 50% of boys age 13-17 years gave a larger reaction to PPD-B. In the soulhern towns of Albany and Manjirnup under 25~/, of boys of the same age group gave a larger reaction to PPD-B. The proportion of children giving a larger reaction to PPD-S is about the same in both areas. Smaller numbers of children under 13 years were tested in each area but results are similar to those noted above. There were no obvious differences in the proportion of children giving larger reactions to PPD-S throughout the Slate. Size Of Reactions Reactions were grouped into three sizes as shown in Table IV. where PPD-B gave the larger reaction the size of this reaction was commonly between 5 and 9 rnm. Larger reactions to PPD-S were commonly over 10 ram. in diameter. The majority of individuals giving a larger reaction to PPD-B have probably not been sensitized by tubercle bacilli (Edwards, Edwards and Palmer, 1959). Of 447 'children giving a 5 to 9 ram. 9reaction to PPD-S as many as 346 (7 7 9",,3 gave a larger reaction to PPD-B. Reaction sizes in boys age 13-17 years in different regions are shown in Fig. 4. There were less reactions to PPD-B in the southern town of Albany but in Derby, further north, 73 9',, of boys reacted to PPD-B and the proportion of larger (I0-12 ram.) reactions was also higher. The size of reactions to PPD-S showed no obvious geographical variation. AGE 13-17_ YEARS
40
~ ' ~ NOT AUSTRALIAN BORN PPD-B>PPD-S PPD-S>PPD-B
30
% 20
Flc. a2g
Proportion oflarger reactions to PPD-B and PPD-S in children
e 13-17 years born in Australia and not born in Atlstralia..
278
TUBERCLE PPD-S > PPD-B 101 o/o
O
r-'-q
~
,----.F~
t-J H
I ! L-rfl..I
60-
r-~
PPD-B> PPD-S
5040 ~
30 20 10
O
D
G
K
N Mi
F HH M A < PERTH >
C Me AL
Key: D-Derby; G-GeraldtoJl; K-Kaigoorlie; N-Northam" Mi-Midland" Perth (3 Schools): A-Armadale; C-Collie: Ma-Manjimup; AL-Albany. FIG. 3 Proportion of larger reactions to PPD-B and PPI)-S in boys age 13-17 years in different localilies in Western Australia.
Discussion
Migrants to this State show a higher incidence o f active p u l m o n a r y tuberculosis born persons (Edwards, 1963). It is likely that the higher p r o p o r t i o n o f larger P P D - S migrant children is associated with increased contact with Mycobacterium tuberculosis native land and after migration. It seems reasonable to regard most o f the larger reactions to P P D - B as being due to
than native reactions in both in their sensitization
TABLE IV.--COMPARATIVE SKIN TESTING OF SCHOOL CHILDREN BY SIZE OF REACI'IONS
! i
Diameter of induration (tmn.) Under5
i PPD-S>PPD-B PPD-S
PPD-B> PPD-s
i 68 (0.5"./.) i 3o025" .(25%) i
304 (2,5%)
5--9
]
lOam, ...... "
FPD-S reaction i 256 (.2.2%) 50 (0.4%)
101 (0.8%. 346 (2"9%) 2,010 9(16%)
:
[
1,107 (9%)
[ I i
Total
i 425 (3"6%) 3,421 (28%) 3,421 (28%)
*Includes children with no reactions to P.PD-S. Percentages based on total number of chlldren tested (11,885).
TUBERCULIN SENSITIVITY
279
by agents other than M. tuberculosis, even though the smaller reaction (to PPD-S) may be large enough to be called 'positive' in other parts of the world. The cause of this type of sensitization remains unknown, although evidence from patients with pulmonary disease and cervical adenitis indicates th'at both Group I! and Group 111 Battey mycobacteria may play a part (Masters a n d Smyth, 1965). The situation is similar to that found in some parts of the United States (Palmer and Edwards, 1962), and in Queensland (Abrahams and Silverstone, 1961). Sensitization to PPD-B is more than twice as common in the northern area of Geraldton than it is in the southern area of Albany and Manijump. Sensitization to PPD-B is less common in Perth, the ALBANY 390
~ _
D__._~ PP B
PPD -S
50 25
BOYS 13-17
75
460
50 25
BOYS 13-17 2._39
75 5 2 r-[-~m-,~._,_ ._.
BOYS 13-17 5_Be
75 50
0
6
12 1'8 24 0 6 12 18 24 MM. O F INDURATION
F~G. 4 Size of reactions to 5 T.U. of PPD-B and of PPD-S in boys age 13-17years in dift~rentregions. largest city in the State, than in primarily agricultural areaswithin 50 miles radius either towards the north or south. This suggests that sensitization to PPD-B is not related to transmission of ini~ection between humans. Similar findings with PPD-B sensitization have been recorded in the United States (Palmer and Edwards, 1962). These workers caution against assuming that a larger reaction to PPD-B represents infection by Battey bacilli. They have found that many other lnycobacterial infections can give a similar reaction and note that results of experimental work on guinea pigs suggest that scotochromogens are important in this respect. Singer and Rodda (1963) found no correlation between Mantoux conversion rate (to old tuberculin) in Queensland and frequency of isolation of mycobacteria from tonsils of children, or specimens ofmilk, dust or mediastinal nodes of ardmals. In the United States the highest incidence of sensitization to PPD-B occurs in the south-east, which also records the highest incidence of disease due to Battey bacilli. The population of Western Australia is small (835,000) and the number of patients is also small (Carruthers and Edwards, 1965} and so estimates of incidence of disease in a given area are assessed with caution. The evidence at
280
TUBERCt, E
present available suggests that the incidence ofdisease due to Barley bacilli is higher in the regions o f G e r a l d t o n and Kalgoorlie and that the highest p r o p o r t i o n o f larger P P D - B reactions is also found in these areas. Similarly there appears to be a low incidence o f disease due to Barley bacilli in the region o f A l b a n y a n d the lowest p r o p o r t i o n o f children giving larger reactions to P P D - B is also f o u n d in that area. The e n v i r o n m e n t a l factors which favour infection o f h u m a n s by Battey bacilli seem also to favour the agent or agents which sensitize, children to P P D - B . N o n - t u b e r c u l o u s sensitization to tuberculin in Western Australia clearly affects the significance of a 'positive' reaction. As an aid to diagnosis c o m p a r a t i v e testing with P P D - B and P P D - S is preferable to a single test using old tuberculin or P P D - S , especially in children. Sensitization by M . t u b e r c u l o s i s is also obviously difficult to delect in epidemiological surveys using a single test. F r o m Table IV it seems that a reaction over 10 ram. in diameter to P P D - S is a b o u t five times m o r e likely to be due to sensitization by tubercle bacilli and a reaction between 5 and 9 ram. is more likely to indicate n o n - t u b e r c u l o u s sensitization. In s u m m a r y a large proportion o f children in Western Australia give a larger reaction to P P D - B than to an equivalent dose o f P P D - S . There are clear geographic difference: in the prevalence o f sensitization to P P D - B and this affects lhe significance of tuberculin lesling. It seems th~,t, in Western Australia, induration over I0 mm~ diameter to 5 TL1 o f P P D - S is likely to indicate sensitization bv M . t t t b e r c , d o s i s . We are grateful to Dr. Lydia Edwards for advice and for making available the PPI)-S and PPI)-B antigens, We also gratefill/y acknoxvledge the help of the Director and many members of the Tuberculosis Control Branch of the Public Health Department, especially Sisters A. Horne and P. Smith who were responsible for most of the skin testing. REFERENCES AtrlRAH^MS,E. W. & StbVEP,STONE,H. (1961). Epidemiological evidence of the preseilce of non-tuberculous sensitivity to tuberculin in Queensland. Tubercle, Load., 42, 487. Ar'J:aONT~, L. F. (1959). Purified protein derivatives (PPD) and other antigens prep;~red from atypical acid-fast bacilli and Nocardia Asteroides. Am. Re,'. Ttrbert'., 79, 284. CARRUTttERS, K. J. M. & Eowaros, F. G. B. (19651. Atypical mycobactcr~ ~ Westerrl Australkt. Am. Rev. resp. Dis., 91 887. EDWARDS, F~ G. B. (1963). Tuberculosis incidence in the non-Australia,~-! ...... ' Y J..4ust., 1~ 501. EDWARDS, L. B., EDWARDS,P. Q., & PALMER. C. F.. ( 19591. Sources o { , sensitivity i~, l,,~iaa~*,~aI~t,l~tllatiot'~s. A summing up of recent epidemiologic research..,Icier, ttd~r162162 -17, p. 77. MaSTerS, P. L., & SMYtl~/, J. T. (1965). A double Mantoux lest appl .,u. ,ing chilthczi for mycobacterkll infections: Its value in distingtiishing infections by auonymous slr~li: 1,st.. " : ; . . J.. I, 16~'~. P^LM~v,, C. E., & EowarDs, L. B. (1962). Geogr,lphic vr in the II~.... ; ,it,t,, .ltivity to tuberculirl (PPD-S) and Zo the Bat~ey antigen (PPD-B) throughout the United States. B , I / ~,, ~ . . . . . :Jerc., 32, 373. S~mEr'r, F. B., & Gt*:sN, J. T. [1941). Tuberculin purified prolein derivati,,~'...I,, Ir Tuberc., 44, 9. SINC;Er, E., & RODDA, G. M. J. (1963). Non-specific sensitization to old tuberculin: Antigenic studies. Tubercle, Load., 44, 268.
G E O G R A P H I C V A R I A T I O N S IN T H E P R E V A L E N C E O F S E N S I T I V I T Y T O P P D - S AND P P D - B IN W E S T E R N A U S T R A L I A By J. T. SMVrlt* and R. M. PORTER fi'om Sir Charh's Gairdner Hospital and The (?hest Clinic, Perth. IVestern Australia
SUMMARY Between I960 and 1966 comparative Mantoux testing using PPD-S and PPD-B was performed on 11,885 school children living in different areas in Western Australia. PPD-B is prepared from Battey mycobacterfa and was diluted before delivetT to us to correspond in protein ~,nd nitrogen content with the PPD-S. The proportion of" school children giving a larger reaction to each antigen increased with age: and boys gave a slightly kigher proportion of larger reactions to both antigens. Geographic variation was seen in two ways. A larger reaction to PPD-S was given by 10% of children not born in Australia and by only 3.I ~ of Australian-born children. This accords with the known higher incidence of pulmonary tuberculosis in migrants to this State. A larger reaction to PPD-B was given by less than 25 ~o of boys age 13-17 years in the southern part of the state and by over 500/,, of boys of the same age group in the northern and eastern parts, which in general have a lower rainfall and higher average temperature. The proportion of larger reactions to PPD-B was lower in Perth, the principal city of the state, than in surrounding agricultural areas. The proportion of childre~ giving a larger i'eaction to PPD-S.showed little geographic variation. In Weslern Australia most reactions under 10 ram. diameter to 5 TU of PPD-S are probably caused by sensitization by agents other than Mycobacterium tuberculosis.
R~SUM~Entre 1960 et 1966, 11.885 6coliers habitant dans difi~rentes r6gions de l'Australie de l'ouest ont 6t6 testds comparativement avec de la .PPD-S et de la PPD-B. Cette d.erni,~re est pr6parde ~ partir d'un bacille Battey et dilu6e avant usage afin que son contenu protdique et azot6 corresponde/l celui de la PPD-S. La proportion d'6coliers r,~agissant ~ l'un ou l'autre antigone augmentait avec l'fige et la proportion de ceux avec des r,~actions plus importa'ntes aux deux antig6nes 6talent 16g~rement sup6rieure chez les gar~;ons. Des variations g6ographiques ont 6t6 remarqu6es dans deux sens. t0% des enfants n6s en. dehors d'Australie r6agissaient plus fortement h la PPD-S, contre 3,1 ~ seulement parmi les Australiens de naissance. Ceci est en accord avec la plus grande incidence de tuberculose pulmonaire commr cnez les immigrants de ce pays. Une rdaction pr6pond6rante/l la PPD-B a 6t6 trouvde chez~moins de 25 % des garqons 5.g6s d e l 3 5.17 arts darts la pattie Nord de l'Etat, et chez plus de 5 0 ~ des gar~;ons du m~me groupe d'fige habitant dans la partie Nord-est, o~ en g6nfral les pluies sont moins abon* Present address: Hawkmoor Chest Hospital, BoveyTracey, Devon.
274
TU~vRCt, V. dantes et la tempfrature moyenne plus 61ev6e. La proportion de r6actions plus forles "h la PPD-B 6tait plus basse fi Perth, principale ville de l'Etat, que dans les r6gions agricoles avoisinantes. La proportion d'enfants reagissant plus ~t la PPD-S n'a montr6 que peu de variations g6ographiques. En Australie de l'Ouest, la plupart des r6actions au-desgous dr, !0 mm. de diam&re ~'~ 5 UT de PPD-S est probablement due ~ une sensibilisation par des organ;~:mes attires que
M. tuberculosis.
RESUMEN Entre 1960 y 1966 se efectuaron reacciones de Mantoux comparadas con PPD-S y PPD-B en I1.885 escolares que vivian en fireas Oiferentes de Australia Occidental. E! PPD-B se prepar6 con mycobacterias Battey y fur diluido antes de llegar a nuestro poder de tal modo que su contenido de proteinas y nitr6geno fuera anfilogo al del PPD-S. La proporci6n de escolares que di6 mayor reacci6n frenle a cada antigeno aument6 con la edad ; por su parte, los nifios varones dieron una discreta mayor proporci6n de reacciones intensas ambos antigenos. Hubo variaciones geogrtificas en ambos sentidos. Hubo una reacci6n mils intensa al PPD-S en el 10~ de los nifios no nacidos en Australia y era el 3'1 o(, de los nacidos eta Australia. Esto coincide con ia conodida mayor incidencia de tuberculosis pulmonar en los int~igrnntes. Hubo una intensa reacci6n al PPD-B en menos del 25~,, de los nifios de 13 a 17 afios en la regi6n sur del estado y e n mils del 50'~,,] de los nifios del mismo grupo etario de las regiones norte y este, regiones que generalmente tienen menor precipitaci6n pluvial y mayor temperatura promedio. La proporci6n de reacclones m~is intensas al PPD-B fu6 m~is baja en Perth, la ciudad principal del estado, que en las ~ireas agricolas circundantes. La proporci6n de nifios con intensa reacci6n al PPD-S mostr6 poca variaci6n geogrtifica. En Australia Occidental la mayoria de las reacciones por debajo de 10 mm. de dihmetro a 5 UT de PPD-S son probablement producidas por la sensibilizacifn a un agentc que no es el Mj,cobacterium tuberculosis.
Introduction In Western Australia about 1()~ of school children give a positive reaction to tuberculin on multiple puncture testing. In Queensland the reaction rate is higher and varies from place to place within the State, probably because of non-tuberculous sensitization (Abrahams and Silverstone, 1961). It seemed likely that non-tuberculous sensitization was present in Western Australia and we report a survey of the incidence of sensitization to PPD-S and PPD-B in school children in different parts of the State. Methods
Study Population School children in widely differing areas of the State were tested (Fig. 1). Through the Director of Tuberculosis Control the programme was integrated with a mass x-ray survey of the population and routine tuberculin testing of school children over the period 1960 to 1966. The age of children tested was from 5-17 years. Co-operation by the school staff, pupils and parents, was very good. 90-95 ,"/oof the total enrolment of each school was tested. Parents were informed of the nature o f the test and requested to give their consent and supply information concerning the country of birth of the child and previous BCG vaccination. Results from children who had had BCG were not included in the survey.
1Ui|t'~('12LtN
S~N$11 t~ 11 Y
27~
AIltlgens were supplied by the U.S. Public H e a h h Service lhro,,i~h lhe courtesy o f D r . Lydia Edwatd~. p P D - S ( i n l e r n a l i o n a l staltdard h u m a n slrain purified protein deri~.ative, Sctberl arld G l e n n , 1941) ~ind P P D - B ",.',ere used. P P D - B is prepared from Batt,2y organisms and was dil u l e d before deliver', to w-. to cerrcspond in protein .and nilro~e,l content v, ith PPD-S ( A f f , o n t i , 1959)9 O n i h i , basis ('J-I n l l of antlgen c olres ponds to 5. T I J s l r e ~ g l h
1 1 1
f
! !
h,,
9 ~gL~letn Auslrall~l. t!,r Io~t,~ ,he *n ,,ca. inclut'r
i
in 1he ~u:~e~ {Instt--LI~- Unlled IK ng~ o, on Ihe ~.n t ~1r
ch~m,cally cleaned b,efor~ us~ [):".po'~,xble 26 gauge llIlr~1-dernl.Jl n~.'cdles were t t ~ ' d Procedure ~t~iections of 0-I mL of each ~mh.cen were gi'.en into lhe flexor surface of each folear.n Almost all the injections were given by a ~"am of four ~lnd reac~iorls were read alter 72 hollrs by the same team. Induration wa~ measured transversely in millirrtelres using dividers and a ruler9 reactions which did not differ by more Ihan 2 ram. were regarded as equal9 Re~Its
Results were analyzed in terms of larger reaetio,ls to each antigen. Reaction ,~ize~wer~ also noted
TUBERCLE
276
TABLE I.--LARGER REACTIONSTO 5 T.U. OF PPD-B OR PPD-S IN DIFFERENTAGE GROUPS Age O'ears) Total 10--12 Total children
1,302
PPD-B > PPD-S PPD-S > PPD-B _._
i
13--17
i
2,651 (!00%) i 7,932 (100%) t. 729 "(27.5%) i 2,389 (30"2~ 56 (2"1%) i 344 (4"40/0)
(100%)
(23.2%) 25 (1.9%) _ 303
iI
I! ,885
.
i i
3.421 425
TABLE II.~I,,ARGER REAL-q'IONgTO 5 T.U. OF PPD-B ANn PPD-S IN BOYSAND GIRLS IN DIFFERENTAGE GROUPS Age groups ()'ears)
Total tested*
I PPD-B> PPD.s [ No.. ~f
PPD-S> PPD-B No. o//,f
[
[
5--9 (Boys) (Girls) 10~12 (Boys) (Girls)
i
13~!7 (.Boys) (Girls) Total
(Boys) (Girls)
.
656 646
i I
165 138
25.0 21 "0
14 I1
2.0 ! .7
1,405 1,246
i 1
405 324
28.2 26.0
33 23
2"3 1-9
4,136 3,786
] 1,514 i 870
36.2 22.7
200 142
4.9 3.7
6,197 5,678
i 2,084 ] 1,332
i
247 176
* Results from 10 children omitted--sex not recorded. "1"Based on the total t~sted in each group. and analyzed separately. Results of comparative testing of 11,885 children were analyzed. A larger reaction to PPD-B was given by 3,421 (28 ~ ) of these. A larger reaction to P P D - S was given by 425 (3.6 ~). Variation with Age The proportion of each age group giving a larger reaction to each antigen is shown in Table I. The proportion of school children giving a larger reaction to each antigen increases with. age. Relation to S e x Results of comparative testing in each age group were analyzed by sex. Results are shown in Table Ii. There is a slightly higher proportion of larger reactions to both antigens amongst boys. Geographic Variations Geographic variation was evident in two ways : - (I) Children not born in Australia showed a higher proportion of larger reactions to PPD-S than children born in Australia (Table l l l and Fig. 2). A larger reaction to PPD-S was given by I0-0 ~ of children not born in Australia and by only 3.1 ~o of Australian born children. The difference is significant. It is possible that some children born overseas had had B C G vaccination which was not recorded by their parents. This factor was unlikely to have influenced the results significantly. (2) Children living in the south of Western Australia had a lower proportion of larger reactions to PPD-B than those living elsewhere (Fig. 3). In Geraldton, Kalgoorlie and
TUBERCULIN SENSITIVITY
277
TABLE III.--COMPARATIVE SKIN TLSTING CttILDREN AGE 13--17 YEARS BORN IN AUSTRALIAAND NOT BORN IN AUSTRALIA Australian horn
Not Australian born
Total children*
6,449 (I00%}
PPD-B>PPD-S
2,064 (32.1~
314 (22"4%)
PPD-S>PPD-B
202 (3"1%)
140 (10"0".~1
!,400
(100~,~)
* Results from 83 children omitted--country of birth not recorded. Derby over 50% of boys age 13-17 years gave a larger reaction to PPD-B. In the soulhern towns of Albany and Manjirnup under 25~/, of boys of the same age group gave a larger reaction to PPD-B. The proportion of children giving a larger reaction to PPD-S is about the same in both areas. Smaller numbers of children under 13 years were tested in each area but results are similar to those noted above. There were no obvious differences in the proportion of children giving larger reactions to PPD-S throughout the Slate. Size Of Reactions Reactions were grouped into three sizes as shown in Table IV. where PPD-B gave the larger reaction the size of this reaction was commonly between 5 and 9 rnm. Larger reactions to PPD-S were commonly over 10 ram. in diameter. The majority of individuals giving a larger reaction to PPD-B have probably not been sensitized by tubercle bacilli (Edwards, Edwards and Palmer, 1959). Of 447 'children giving a 5 to 9 ram. 9reaction to PPD-S as many as 346 (7 7 9",,3 gave a larger reaction to PPD-B. Reaction sizes in boys age 13-17 years in different regions are shown in Fig. 4. There were less reactions to PPD-B in the southern town of Albany but in Derby, further north, 73 9',, of boys reacted to PPD-B and the proportion of larger (I0-12 ram.) reactions was also higher. The size of reactions to PPD-S showed no obvious geographical variation. AGE 13-17_ YEARS
40
~ ' ~ NOT AUSTRALIAN BORN PPD-B>PPD-S PPD-S>PPD-B
30
% 20
Flc. a2g
Proportion oflarger reactions to PPD-B and PPD-S in children
e 13-17 years born in Australia and not born in Atlstralia..
278
TUBERCLE PPD-S > PPD-B 101 o/o
O
r-'-q
~
,----.F~
t-J H
I ! L-rfl..I
60-
r-~
PPD-B> PPD-S
5040 ~
30 20 10
O
D
G
K
N Mi
F HH M A < PERTH >
C Me AL
Key: D-Derby; G-GeraldtoJl; K-Kaigoorlie; N-Northam" Mi-Midland" Perth (3 Schools): A-Armadale; C-Collie: Ma-Manjimup; AL-Albany. FIG. 3 Proportion of larger reactions to PPD-B and PPI)-S in boys age 13-17 years in different localilies in Western Australia.
Discussion
Migrants to this State show a higher incidence o f active p u l m o n a r y tuberculosis born persons (Edwards, 1963). It is likely that the higher p r o p o r t i o n o f larger P P D - S migrant children is associated with increased contact with Mycobacterium tuberculosis native land and after migration. It seems reasonable to regard most o f the larger reactions to P P D - B as being due to
than native reactions in both in their sensitization
TABLE IV.--COMPARATIVE SKIN TESTING OF SCHOOL CHILDREN BY SIZE OF REACI'IONS
! i
Diameter of induration (tmn.) Under5
i PPD-S>PPD-B PPD-S
PPD-B> PPD-s
i 68 (0.5"./.) i 3o025" .(25%) i
304 (2,5%)
5--9
]
lOam, ...... "
FPD-S reaction i 256 (.2.2%) 50 (0.4%)
101 (0.8%. 346 (2"9%) 2,010 9(16%)
:
[
1,107 (9%)
[ I i
Total
i 425 (3"6%) 3,421 (28%) 3,421 (28%)
*Includes children with no reactions to P.PD-S. Percentages based on total number of chlldren tested (11,885).
TUBERCULIN SENSITIVITY
279
by agents other than M. tuberculosis, even though the smaller reaction (to PPD-S) may be large enough to be called 'positive' in other parts of the world. The cause of this type of sensitization remains unknown, although evidence from patients with pulmonary disease and cervical adenitis indicates th'at both Group I! and Group 111 Battey mycobacteria may play a part (Masters a n d Smyth, 1965). The situation is similar to that found in some parts of the United States (Palmer and Edwards, 1962), and in Queensland (Abrahams and Silverstone, 1961). Sensitization to PPD-B is more than twice as common in the northern area of Geraldton than it is in the southern area of Albany and Manijump. Sensitization to PPD-B is less common in Perth, the ALBANY 390
~ _
D__._~ PP B
PPD -S
50 25
BOYS 13-17
75
460
50 25
BOYS 13-17 2._39
75 5 2 r-[-~m-,~._,_ ._.
BOYS 13-17 5_Be
75 50
0
6
12 1'8 24 0 6 12 18 24 MM. O F INDURATION
F~G. 4 Size of reactions to 5 T.U. of PPD-B and of PPD-S in boys age 13-17years in dift~rentregions. largest city in the State, than in primarily agricultural areaswithin 50 miles radius either towards the north or south. This suggests that sensitization to PPD-B is not related to transmission of ini~ection between humans. Similar findings with PPD-B sensitization have been recorded in the United States (Palmer and Edwards, 1962). These workers caution against assuming that a larger reaction to PPD-B represents infection by Battey bacilli. They have found that many other lnycobacterial infections can give a similar reaction and note that results of experimental work on guinea pigs suggest that scotochromogens are important in this respect. Singer and Rodda (1963) found no correlation between Mantoux conversion rate (to old tuberculin) in Queensland and frequency of isolation of mycobacteria from tonsils of children, or specimens ofmilk, dust or mediastinal nodes of ardmals. In the United States the highest incidence of sensitization to PPD-B occurs in the south-east, which also records the highest incidence of disease due to Battey bacilli. The population of Western Australia is small (835,000) and the number of patients is also small (Carruthers and Edwards, 1965} and so estimates of incidence of disease in a given area are assessed with caution. The evidence at
280
TUBERCt, E
present available suggests that the incidence ofdisease due to Barley bacilli is higher in the regions o f G e r a l d t o n and Kalgoorlie and that the highest p r o p o r t i o n o f larger P P D - B reactions is also found in these areas. Similarly there appears to be a low incidence o f disease due to Barley bacilli in the region o f A l b a n y a n d the lowest p r o p o r t i o n o f children giving larger reactions to P P D - B is also f o u n d in that area. The e n v i r o n m e n t a l factors which favour infection o f h u m a n s by Battey bacilli seem also to favour the agent or agents which sensitize, children to P P D - B . N o n - t u b e r c u l o u s sensitization to tuberculin in Western Australia clearly affects the significance of a 'positive' reaction. As an aid to diagnosis c o m p a r a t i v e testing with P P D - B and P P D - S is preferable to a single test using old tuberculin or P P D - S , especially in children. Sensitization by M . t u b e r c u l o s i s is also obviously difficult to delect in epidemiological surveys using a single test. F r o m Table IV it seems that a reaction over 10 ram. in diameter to P P D - S is a b o u t five times m o r e likely to be due to sensitization by tubercle bacilli and a reaction between 5 and 9 ram. is more likely to indicate n o n - t u b e r c u l o u s sensitization. In s u m m a r y a large proportion o f children in Western Australia give a larger reaction to P P D - B than to an equivalent dose o f P P D - S . There are clear geographic difference: in the prevalence o f sensitization to P P D - B and this affects lhe significance of tuberculin lesling. It seems th~,t, in Western Australia, induration over I0 mm~ diameter to 5 TL1 o f P P D - S is likely to indicate sensitization bv M . t t t b e r c , d o s i s . We are grateful to Dr. Lydia Edwards for advice and for making available the PPI)-S and PPI)-B antigens, We also gratefill/y acknoxvledge the help of the Director and many members of the Tuberculosis Control Branch of the Public Health Department, especially Sisters A. Horne and P. Smith who were responsible for most of the skin testing. REFERENCES AtrlRAH^MS,E. W. & StbVEP,STONE,H. (1961). Epidemiological evidence of the preseilce of non-tuberculous sensitivity to tuberculin in Queensland. Tubercle, Load., 42, 487. Ar'J:aONT~, L. F. (1959). Purified protein derivatives (PPD) and other antigens prep;~red from atypical acid-fast bacilli and Nocardia Asteroides. Am. Re,'. Ttrbert'., 79, 284. CARRUTttERS, K. J. M. & Eowaros, F. G. B. (19651. Atypical mycobactcr~ ~ Westerrl Australkt. Am. Rev. resp. Dis., 91 887. EDWARDS, F~ G. B. (1963). Tuberculosis incidence in the non-Australia,~-! ...... ' Y J..4ust., 1~ 501. EDWARDS, L. B., EDWARDS,P. Q., & PALMER. C. F.. ( 19591. Sources o { , sensitivity i~, l,,~iaa~*,~aI~t,l~tllatiot'~s. A summing up of recent epidemiologic research..,Icier, ttd~r162162 -17, p. 77. MaSTerS, P. L., & SMYtl~/, J. T. (1965). A double Mantoux lest appl .,u. ,ing chilthczi for mycobacterkll infections: Its value in distingtiishing infections by auonymous slr~li: 1,st.. " : ; . . J.. I, 16~'~. P^LM~v,, C. E., & EowarDs, L. B. (1962). Geogr,lphic vr in the II~.... ; ,it,t,, .ltivity to tuberculirl (PPD-S) and Zo the Bat~ey antigen (PPD-B) throughout the United States. B , I / ~,, ~ . . . . . :Jerc., 32, 373. S~mEr'r, F. B., & Gt*:sN, J. T. [1941). Tuberculin purified prolein derivati,,~'...I,, Ir Tuberc., 44, 9. SINC;Er, E., & RODDA, G. M. J. (1963). Non-specific sensitization to old tuberculin: Antigenic studies. Tubercle, Load., 44, 268.