Jornal Brasileiro de Pneumologia 3 0 (4 ) - Jul/ Ago de 2 0 0 4
Efficiency of clinical, radiological and laboratory testing
in the diagnosis of pleural tuberculosis*
DENISE DUPRAT NEVES, RICARDO MARQUES DIAS, ANTÔNIO JOSÉ LEDO ALVES DA CUNHA, ANTONIO MONTEIRO DA SILVA CHIBANTE(TE SBPT)
Background: In Brazil, tuberculosis is the major cause of pleural effusion. In more than 50% of cases, treatment has
been initiated prior to confirmation of the diagnosis. Our objective was to identify factors that can contribute to the diagn osis.
Method: We studied 215 consecutive patients with pleural effusion: 104 from tuberculosis (TB) and 111 from other
causes (41 were from malignancies, 29 involved transudation, 28 were parapneumonic and 13 were from other etiologies). Clinical, radiological and laboratorial variables were evaluated for differences between the two groups, individually or in combin at ion .
Results: Male gen der an d PPD > 10 m m were sign ifican t ly m ore frequ en t in t he t u bercu losis grou p. Radiological feat u res were sim ilar in bot h grou ps. Am on g t he con t in u ou s variables, aden osin e deam in ase (ADA), percen t ile of cells, prot ein an d age perform ed bet t er as isolat ed diagn ost ic crit eria. Bet ween t he grou p wit h t u bercu losis an d t hat wit h pleu ral effu sion from ot her cau ses, n o sign ifican t differen ces were fou n d in Lact at e dehydrogen ase, t ot al leu ko cyt es o r d u ra t io n o f d isea se. Th e co rrela t io n o f ADA wit h a n y o t h er well- d evelo p ed co n t in u o u s va ria b le showed an LR+ > 10 an d an LR- < 0.1, which effect ively con firm ed or ru led ou t a diagn osis of t u bercu lou s pleu ral effu sion .
Conclusions: In patients with ADA levels > 39 at 95% sensitivity, the specificity can be improved to more than 90% if
we consider non purulent effusion or effusion with a predominance of lymphocytes (> 50%).
Key words: Tuberculosis, pleural/diagnosis. Adenosine deaminase/diagnosis use. Sensitivity and specificity.
*St u d y ca rried o u t a t t h e Ho sp it a l Un iversit á rio Ga ffrée e Gu in le (Ga ffrée a n d Gu in le Un iversit y Ho sp it a l) - Un iversid a d e Fed era l d o Est a d o d o Rio d e J a n eiro (UNIRIO, Rio d e J a n eiro Fed era l Un iversit y) in Rio d e J a n eiro , RJ .
Co rresp o n d en ce t o : Den ise Du p ra t Neves. Ru a Ma riz e Ba rro s 7 7 5 , Ho sp it a l Un iversit á rio Ga ffrée e Gu in le, DEMESP, Pn eu m o lo g ia . Tiju ca , Rio d e J a n e iro . Bra z il. CEP 2 0 2 7 0 - 0 0 4 . Ph o n e : 5 5 2 1 2 5 6 9 7 610 . E- m a il: d d u p ra t @ u n irio .b r
st an dard for et iologic diagn osis of pleu ral effu sion , a lt h o u g h t im e c o n s u m in g a n d o f m o d e ra t e s e n s it ivit y(3 - 5 ). As a r e s u lt , t h e p r e s e n c e o f
g ra n u lo m a co m b in ed wit h ca seo u s n ecro sis is accep t ed as a d iag n o st ic crit erio n an d h as b een co n sid ered d efin it ive, esp ecia lly in a rea s wh ere t u b ercu lo sis is h ig h ly p revalen t (3 ,5 - 7 ). Even if we co n sid er t h ese t wo crit eria, t h at is, cu lt u re an d h is t o p a t h o lo g ic a l e xa m in a t io n , a d e f in it ive d iag n o sis is o n ly m ad e in ap p ro xim at ely 8 5 % o f cases(8 ). In p ract ice, efficien cy can b e even lo wer.
Dat a fro m t h e cit y o f Rio d e J an eiro revealed t h at , in a g reat n u m b er o f cases (ap p ro xim at ely 5 0 %), t reat m en t was in it iat ed p rio r t o co n firm at io n o f t h e d iag n o sis(9 ).
Am o n g o t h e r n e w d ia g n o s t ic m e t h o d s , d e t e rm in a t io n o f a d e n o sin e d e a m in a se (ADA) act ivit y h as b een h ig h lig h t ed in t h e d iag n o sis o f p leu ral t u b ercu lo sis b ecau se o f it s h ig h sen sit ivit y (> 9 0 % ). Mo s t s t u d ie s h a ve c o n f ir m e d t h e u sefu ln ess of t his m et hod an d have recom m en ded it s u se in t h e ro u t in e in vest ig a t io n o f p leu ra l t u bercu losis, even in pat ien t s in fect ed wit h hu man im m u n o d eficien cy viru s (HIV), esp ecially in areas w h e re p re va le n ce o f t h e d ise a se is h ig h(1 0 ,11 ). H o w e ve r, d u e t o i t s m o d e r a t e s p e c i f i c i t y (a p p ro xim a t e ly 8 5 % ), t h is d ia g n o st ic m e t h o d can n o t b e u sed in iso lat io n . Th erefo re, in o rd er t o im p ro ve t h e efficien cy o f t h e t est , it s h as b een su ggest ed t hat it be u sed in combin at ion wit h ot her clin ical an d laboratory criteria(2,7,10- 19). Un fortu n ately, t h ese crit eria, as well as an accep t ab le p ro b ab ilit y valu e, h ave yet t o b e est ab lish ed .
Th e m ain o b ject ive o f t h e p resen t st u d y was t o evalu at e t he efficien cy of clin ical, radiological an d la b o ra t o ria l t est in g in t h e d ia g n o sis o f p leu ra l t u bercu losis.
METHOD
Th i s w a s a t r a n s v e r s a l s t u d y i n w h i c h co n secu t ive p at ien t s su b m it t ed t o ro u t in e t est in g for t he diagn ost ic in vest igat ion of pleu ral effu sion a t t h e Ho sp it a l Un iversit á rio Ga ffrée e Gu in le
(Gaffrée an d Gu in le Un iversit y Ho sp it al) o f t h e
Un iversid ad e Fed eral d o Est ad o d o Rio d e J an eiro
(Rio d e J an eiro Fed eral Un iversit y) were in clu d ed . Pat ien t s fo r wh o m ADA co u ld n o t b e d et erm in ed o r fo r wh o m a d efin it ive d iag n o sis co u ld n o t b e m ad e, as well as t h o se p at ien t s wh o h ad b een p revio usly in clu d ed in t h e st u d y, were exclu d ed .
Jornal Brasileiro de Pneumologia 3 0 (4 ) - Jul/ Ago de 2 0 0 4
The det ermin at ion of ADA levels in pleu ral flu id was performed in du plicat e in accordan ce wit h t he t e c h n iq u e d e s c r ib e d b y Giu s t i(2 6 ). Af t e r cen t rifu gat ion , su pern at an t was st ored at - 20oC in a freezer, with no addition of anticoagulants. A blank was prepared for every sample. Blanks for the control of su bst rat e an d reagen t s were prepared daily.
We c a lc u la t e d t h e f re q u e n c y o f n o m in a l variables, as well as cen t ral measu res, dispersion , a n d r a n g e o f c o n t in u o u s va r ia b le s f o r t h e p re se n t a t io n o f sa m p le ch a ra ct e rist ics a n d o f variables per grou p. The chi- squ are t est was u sed for nominal variables and Mann- Whitney or Kruskal-Wallis t est s were u sed for con t in u ou s variables. Valu es of p < 0.05 were con sidered st at ist ically sign ifican t (reject ion of t he n u ll hypot hesis). Odds rat ios an d t he propert ies of diagn ost ic t est in g were calcu lat ed from 2X2 con t in gen cy t ables, an d t he greatest discriminatory power was determined using t he receiver operat in g charact erist ic (ROC) cu rve.
The Et hics Research Commit t ee of t he Hospit al Universitário Gaffrée e Guinle approved this study in 1998, in accordance with resolution 196/96 released b y t h e Dep a rt m en t o f Hea lt h . Th is st u d y wa s u n spon sored an d t here was n o con flict of in t erest .
RESULTS
Th e st u d y co m p rised 2 9 4 co n secu t ive p leu ral effu sio n p at ien t s su b m it t ed t o p leu ral p u n ct u re. Of t h ese, 4 2 were exclu d ed b ecau se ADA levels co u ld n o t b e d et erm in ed , an d 5 were exclu d ed b e c a u se t h e y h a d b e e n p re vio u sly in c lu d e d . An o t h er 3 2 p at ien t s were exclu d ed b ecau se t h e d iag n o sis was u n co n firm ed , alt h o u g h 1 7 o f t h ese were co n sid ered p ro b ab le cases o f t u b ercu lo sis.
Of t h e 2 1 5 cases in clu d ed in t h e st u d y, 10 4 (4 8 % ) we re d ia g n o se d wit h t u b e rcu lo sis (TB g ro u p ), a n d t h e re m a in in g 111 (5 2 % ) w e re d i a g n o s e d w i t h o t h e r d i s e a s e s t h a t w e r e n o n t u b ercu lo u s (NTB g ro u p ). In t h e NTB g ro u p , p leu ral effusio n resu lt ed fro m m alig n an cies in 41 p a t ie n t s (1 9 .1 % o f t h e t o t a l sa m p le : 7 wit h l y m p h o m a a n d 3 4 w i t h m e t a s t a s e s ) a n d t ran su d at io n in 2 9 (1 3 .5 %). In t h e sam e g ro u p , 28 pat ien t s (13%) were parapn eu m on ic (12 sim ple cases an d 1 6 wit h co m p licat io n s), wh ich resu lt ed in t h eir p leu ral effu sio n . Th e rem ain in g 1 3 NTB p at ien t s (6 %) p resen t ed o t h er et io lo g ies: 3 wit h syst em ic lu p u s eryt h em at o su s, 2 wit h p u lm o n ary t h ro m b o em b o lism , 2 wit h p a n crea t it is, 1 wit h
h em it h o rax, 1 wit h ch ylo t h o rax, 1 wit h Dressler’s syn d ro m e, 1 wit h en d o m et rio sis, 1 wit h ch ro n ic ren al d isease, an d 1 wit h liver d isease).
Frequ en cy of n omin al variables in t he grou ps is shown in Table 1. There was a predomin an ce of males in t he sample (male/ female rat io of 2.7:1 in t he TB grou p an d 1.1:1 in t he NTB grou p). A higher proportion of males was also found in the subgroups, su ch as in pat ien t s wit h parapn eu mon ic effu sion . However, there was no significant difference between t his su bgrou p an d t he TB grou p (p = 0.4988).
Radiological fin din gs revealed t hat effu sion du e t o t u bercu losis was t ypically u n ilat eral an d most ly presen t in t he right hemit horax. However, t here was n o sign ifican t differen ce bet ween t he TB an d NTB groups. In patients with transudation, most effusions (69%) were fou n d in t he right hemit horax, an d t he in ciden ce was sign ifican t ly higher t han in t he TB grou p (p < 0.0001). Bilat eral effusions were t wo an d a half t imes more frequ en t in t he NTB grou p, especially in t he cases in volvin g t ran su dat ion an d t hose secon dary t o syst emic diseases. No sign ifican t differen ce was fou n d in effu sion volu me bet ween t he TB an d NTB grou ps (p = 0.1802), alt hou gh massive effu sion s were more frequ en t in t he NTB grou p. In ciden ce of paren chymal lesion s was higher in t he NTB grou p, bu t t here was n o sign ifican t differen ce in comparison wit h t he TB grou p (p = 0.0753). Radiography revealed lesion s in 16 (40%) of t he 41 cases in volvin g malign an cies (4 cases of lym p h o m a a n d 1 2 o f m e t a st a sis), wh ich wa s sig n ifican t ly h ig h er t h an in t h e TB g ro u p (p = 0 .0 0 5 6 ). Lesio n s were a lso p resen t in 3 3 % o f pat ien t s in t he parapn eu mon ic su bgrou p, alt hou gh t his in ciden ce was n ot higher t han in t he TB grou p (p = 0.1384).
On ly 5 2 p at ien t s (41 %) were su b m it t ed t o PPD skin t est s. Th e few weak resp o n ses were st u d ied co n co m it an t ly wit h n eg at ive resu lt s. In cid en ce o f s t r o n g r e a c t io n (in d u r a t io n > 1 0 m m ) w a s sig n ifican t ly h ig h er in t h e TB g ro u p (7 6 %) t h an in t h e NTB g ro u p (p = 0 .0 0 0 8 ).
Table 2 shows sign ifican t differen ces of cen t ral m easu res b et ween TB an d NTB g ro u p s, as well as t h e g reat est d iscrim in at o ry p o wer an d t h e area b elo w t h e ROC cu rve fo r co n t in u o u s variab les.
TABLE 1
Nominal variables in the TB and NTB g roups
Va ria b le TB NTB
group group
N % N %
GENDER
Ma le 76 3 5 ,3 5 % 60 2 7 ,91 %
Fem ale 28 1 3 ,0 2 % 51 2 3 ,7 2 %
X- RAY (SIDE)
Rig h t 57 2 6 ,51 % 64 2 9 ,7 7 %
Left 43 2 0 ,0 0 % 36 1 6 ,7 4 %
Bila t e ra l 4 1,86% 11 5,12%
X- RAY (VOLUME)
< 1 / 3 HT 39 1 8 ,1 4 % 51 2 3 ,7 2 %
Bet ween 1 / 3 a n d 2 / 3 35 1 6 ,2 8 % 25 11 ,6 3 %
> 2 / 3 HT 30 1 3 ,9 5 % 35 1 6 ,2 8 %
X- RAY (LESION)
Absen t 84 4 0 ,3 8 % 75 3 6 ,0 6 %
Present 18 8,65% 31 1 4 ,9 0 %
PPD
No n - react ive 9 11 ,2 4 % 19 2 1 ,3 5 %
Wea k resp o n se 5 5,62% 5 5,62%
St ro n g resp o n se 38 4 2 ,7 0 % 12 1 3 ,4 8 %
PPD: p u rified p ro t ein d eriva t ive; TB: t u b ercu lo sis; NTB: n o n t u b ercu lo u s; HT: h em it h o ra x
TABLE 2
Characteristics of continuous variables
Va ria b le TB NTB p Valu e AUC 9 5 % CI
group group
Ag e 80,02 134,21 0,0001 < 4 5 0,752 0 ,6 8 9 a 0 ,8 0 8
Time 97,61 113,7 0,0558 < 4 5 0,576 0 ,5 0 7 a 0 ,6 4 4
Prot ein 133,28 83,13 0,0001 > 4 ,1 0,734 0 ,6 7 0 a 0 ,7 9 2
LDH 108,08 86,7 0,0079 > 2 9 8 0,611 0 ,5 3 8 a 0 ,6 8 0
Leu kocyt es 99,99 98,12 0,8179 < 6 0 0 0 0,491 0 ,41 9 a 0 ,5 6 3
Lymphocyt es 136,91 77,76 0,0001 > 81 0,799 0 ,71 7 a 0 ,8 3 3
PMN 78,53 132,93 0,0001 < 1 8 0,757 0 ,6 9 3 a 0 ,81 3
ADA 152,72 66,1 0,0001 > 3 9 0,903 0 ,8 5 5 a 0 ,9 3 9
TB: t u b ercu lo sis (m ed ia n ); NTB: n o n t u b ercu lo u s (m ed ia n ); AUC: a rea u n d er t h e receiver o p era t in g ch a ra ct erist ic cu rve; 9 5 % CI: 9 5 % co n fid en ce in t erva l; LDH: la ct a t e d eh yd ro g en a se. PMN: p o lym o rp h o n u clea r; ADA: a d en o sin e d ea m in a se
in b o t h TB an d NTB g ro u p s, t h ere were ext rem e v a l u e s i n t h e N TB g r o u p , s h o r t e r i n t h e parapn eu mon ic su bgrou p (median of 18 days), an d lo n g er in t h e case o f m alig n an cies (m ed ian o f 6 0
Jornal Brasileiro de Pneumologia 3 0 (4 ) - Jul/ Ago de 2 0 0 4
TABLE 3
Comparison of efficiency in the differentiation betw een TB and NTB
X2 p OR 95%CI Accu racy SE 95%CI SP 95%CI
Gen d er 7,561 0,006 2,31 1,25- 4,26 59,1 73,1 66- 80 45,9 39- 52
XR sid e 0,753 0,386 0,75 0,41- 1,37 51,6 57,0 49- 64 36,0 29- 43
XR U/ B 2,179 0,140 2,75 0,77- 10,64 46,5 96,2 92- 99 9 ,9 3- 12
XR vo lu m e 0,078 0,780 1,14 0,61- 2,12 50,7 71,2 64- 78 31,5 25- 38
XR lesio n 3,266 0,070 1,93 0,95- 3,93 55,3 82,4 76- 88 29,2 23- 35
PPD 12,062 0,001 5,28 1,94- 14,67 70,0 71,7 62- 79 67,6 54- 79
Ag e 39,042 0,0001 6,90 3,56- 13,50 71,2 80,8 74- 87 62,2 56- 68
Time 7,944 0,005 2,69 1,32- 5,53 57,8 84,2 78- 90 33,6 28- 39
Prot eín 39,022 0,0001 7,66 3,77- 15,78 70,5 85,6 79- 91 56,4 50- 61
LDH 11,834 0,001 2,99 1,56- 5,76 62,2 74,2 67- 81 51,0 44- 57
Leu kocyt e 11,755 0,001 10,17 2,18- 65,23 55,8 97,9 93- 99 18,3 14- 20
Lymphocyt e 47,333 0,0001 10,39 4,85- 22,64 72,6 88,4 82- 93 57,8 52- 62
PMN cells 41,013 0,0001 8,95 4,19- 19,45 70,8 88,4 82- 93 54,1 48- 59
ADA 129,046 0,0001 95,87 31,89- 310,57 88,8 95,2 90- 98 82,9 78- 86
X2:chi- squ are t est ; OR: odds rat io; 95% CI: 95% con fiden ce in t erval; SE: sen sit ivit y; SP: specificit y; XR: X- ray; U: u n ilat eral; B:
bilateral; PPD: pu rified protein derivative; LDH: lactate dehydrogen ase; PMN: polymorphon u clear; ADA: aden osin e deamin ase
sig n ifican t ly d ifferen t t h an in t h e TB g ro u p (p = 0 .0 01 7 ). La ct a t e d e h yd ro g e n a se le ve ls va rie d am o n g t h e g ro u p s an d su b g ro u p s. Sig n ifican t ly higher valu es were fou n d in t he TB grou p. However, t h is d ifferen ce was d u e t o t h o se cases in vo lvin g t ran su dat ion . When t he t ran su dat ion su bgrou p was exclu d ed fro m t h e NTB g ro u p , t h e d ifferen ce was n o t sig n ifican t (p = 0 .9 7 4 8 ).
To t a l l e u k o c y t e c o u n t s a n d l a c t a t e d eh yd ro g en a se levels sh o wed wid e ra n g es, a n d t h ere were n o st at ist ically sig n ifican t d ifferen ces b e t w e e n t h e TB a n d N TB g r o u p s . In t h e t ra n su d a t io n a n d p a ra p n e u m o n ic su b g ro u p s, cyt o m et ry valu es were sig n ifican t ly d ifferen t t h an t h o se fo u n d in t h e TB g ro u p (p < 0 .0 0 01 ). In m o st TB g ro u p p at ien t s (9 7 %), leu ko cyt e co u n t s were lo wer t h an 6 0 0 0 cells/ m m3, wh ereas t h ey were higher than that in 68% of parapneumonic patients. Lymphocyt e cou n t s were sign ifican t ly higher in t he TB grou p t han in t he NTB grou p or in an y NTB su bgrou p: t ransu dat ion (p = 0.0051), malign an cy (p = 0.0007), parapn eu m on ic (p < 0.0001) an d ot hers (p < 0.0001). Lymphocyt es predomin at ed in 99% of TB grou p pat ien t s (more t han 50% in t he differen t ial cou n t ), 59% wit h lymphocyt e cou n t s h ig h er t h a n 9 0 % . On ly 2 0 % o f t h e ca ses h a d lymphocyt e cou n t s higher t han 90% in t he NTB grou p. Polymorphon u clear (PMN) cells exhibit ed complemen tary behavior in relation to lymphocytes. All 9 cases wit h PMN cou n t s higher t han 90% were in t he NTB grou p (wit h complicat ion s or empyema).
Higher ADA act ivit y was fou n d in t he TB grou p, con st it u t in g sign ifican t differen ces in comparison t o t he NTB grou p an d t o t he NTB su bgrou ps (p < 0.0001 for t he malign an cy, t ransu dat ion , an d ot her su b g ro u p s; p = 0 .0 0 0 5 fo r t h e p a ra p n eu m o n ic su bgrou p). The ADA valu es were higher t han 39 U/ L in 98 patients from the TB group and in 19 patients from t he NTB grou p: 13 in t he parapn eu m on ic su bgrou p (1 simple, 1 wit h complicat ions an d 11 wit h e m p ye m a ), 3 wit h m a lig n a n cie s (2 wit h lym p h o m a a n d 1 w it h m e t a s t a s is ), 1 w it h t r a n s u d a t io n , a n d 2 w it h o t h e r e t io lo g ie s (pan creat it is an d syst emic lu pu s eryt hemat osu s).
Table 3 su mmarizes power of t he variables t o discrimin at e bet ween TB an d NTB u sin g t he chi-squ are t est an d odds rat io, as well as t he main propert ies as diagn ost ic t est in g. We fou n d t hat t he incidence of strong reaction to PPD skin test and the proport ion of males were higher in t he TB grou p. However, on ly PPD skin t est presen t ed accu racy higher t han 70%. Con t in u ou s variables – especially ADA levels, cytometry, protein levels, and age – proved more efficien t in dicat ors of pleu ral t u bercu losis.
TABLE 4
Efficiency of ADA in effusions not caused by empyema in combination w ith other variables
N
TB NTB D AUC SE SP LR+
LR-No p u s 104 97 38,5 0,965 95,2 91,7 11,54 0,05
LYM > 5 0 102 74 38,5 0,967 95,1 94,6 17,59 0,05
LYM > 8 0 91 47 38,5 0,989 97,8 97,9 45,92 0,02
PTN > 4 ,1 89 48 39 0,869 94,4 77,1 4,12 0,07
Ag e < 4 5 84 42 30,5 0,868 98,8 76,2 4,15 0,02
ADA: ad en o sin e d eam in ase; TB: t u b ercu lo sis; NTB: n o n t u b ercu lo u s; AUC: area u n d er t h e receiver o p erat in g ch aract erist ic cu rve; D: discrim in at ory p o wer; LYM: lym p h o cyt e co u n t ; PTN: p ro t ein ; SE: sen sit ivit y; SP: sp ecificit y; LR: likelih o o d ra t io
be simple, rapid, in expen sive an d easily performed, allo win g t h em t o b e wid ely u sed , even in areas wit h p o o r so cio eco n o m ic co n d it io n s. Sp eed an d p recisio n are m u t u ally exclu sive ch aract erist ics in cu rre n t t u b e rcu lo sis t e st in g m e t h o d s(2 7 ). Th is problem is compou n ded in cases of ext rapu lmon ary t u b ercu lo sis, in wh ich co n firm at io n o f d iag n o sis is m o re d ifficu lt .
Ag e, p ro t ein levels, lym p h o cyt e co u n t s, PMN co u n t s an d ADA levels p ro ved t o b e co n sist en t ly u s e f u l a s d ia g n o s t ic t e s t s in is o la t io n . In d ifferen t ia t in g b et ween t u b ercu lo sis a n d o t h er cau ses of pleu ral effu sion , t hese variables presen t ed sign ifican t differen ces in cen t ral measu res bet ween g ro u p s, h ig h er valu es in t h e area u n d er t h e ROC cu rve (> 0 .7 ), h ig h er accu racy (o ver 7 0 %), h ig h er o d d s rat io (ab o ve 5 ) an d h ig h er m in im al 9 5 % CI (g reat er t h an 3 .5 ). Th ese fin d in g s are q u it e sim ilar t o t hose described in t he lit erat u re, especially when co m p ared t o a st u d y carried o u t in São Pau lo(1 0 ), wh ich id en t ified t h e sam e t est s as relevan t fo r t h e d iag n o sis o f p leu ral effu sio n . Ot h er au t h o rs h ave su g g est ed t h e u se o f t h ese t est s, b o t h in iso lat io n an d in co m b in at io n(1 0 ,1 4 ,1 5 ,2 7 - 3 0 ).
Det erm in a t io n o f ADA levels wa s t h e m o st efficien t t est an d t h e o n ly o n e t h at co u ld p o ssib ly b e u sed in iso lat io n fo r t h e d iag n o sis o f p leu ral t u bercu losis. The sen sit ivit y of ADA det erm in at ion was 9 5 % (9 5 % CI o f 9 0 % t o 9 8 %), wh ich is in acco rd an ce wit h wh at h as b een d escrib ed in t h e lit erat u re (95% CI of 88% t o 100%). If we con sider
o f t u b ercu lo sis . Th erefo re, it is im p o rt an t t hat we iden t ify t he possible cau ses for t he in crease o f ADA act ivit y so t h at t h ese cau ses are t aken in t o con siderat ion when t here is an in crease in en zym e levels. In creased ADA levels h ave b een relat ed t o p le u ra l e ffu sio n s re su lt in g fro m t u b e rcu lo sis, rh eu m at o id effu sio n (wh ich is rare), as well as t o so m e ca se s o f p le u ra l e f f u sio n se co n d a ry t o lymphoma or leu kemia, an d in most cases of pleu ral effu sio n cau sed b y em p yem a(1 ,3 2 - 3 5 ).
Sin ce parapn eu mon ic effu sion s resu lt in g from em p yem a , a s well a s effu sio n s resu lt in g fro m tuberculosis, are most often related to increased ADA levels, t hey have been exclu ded from case an alyses by some au t hors becau se t hey are easily iden t ified an d do n ot sign ifican t ly affect t he u se of t his t est in clin ical pract ice(10 ,11 ,3 6 ,3 7 ). When we exclu ded t hese cases from an alysis in t he presen t st u dy, specificit y in creased an d sen sit ivit y was u n affect ed.
Jornal Brasileiro de Pneumologia 3 0 (4 ) - Jul/ Ago de 2 0 0 4
high in initial effusions(39). Using high ADA values, lymphocyte proportions higher than 80% and greatest discriminatory power (determined from the ROC curve a n d u sed b y o t h er a u t h o rs)(4 0 ,4 1 ), we ru led o u t tuberculous effusion in 12 cases, and other types (in clu d in g p a ra p n e u m o n ic e ffu sio n in vo lvin g complications, as well as pleural effusion resulting from pancreatitis, thromboembolism or empyema) in 47 cases. Due to its lower sensitivity, this combination reduced the chance for making a definitive diagnosis of t u bercu losis, alt hou gh t here was a sign ifican t increase in specificity (to more than 97%), with only one false positive diagnosis (lymphoma). Using the criteria of high ADA values combined with lymphocyte proportions higher than 50% has been reported to increase specificity with no loss of sensitivity(30). In the present study, leukocyte proportions were higher than 50% in the differential counts of 99% of the TB group patients. Sensitivity of ADA levels remained the same (95%) in this group, and specificity increased to 94.6%, with 4 false- positive diagnoses (2 lymphomas, 1 metastasis, and 1 parapneumonic effusion).
The combination of ADA levels and protein levels in pleural fluid and their relationship with serum protein levels could be used in the differential diagnosis between t u b e rcu lo sis a n d m a lig n a n cie s, e sp e cia lly lymphomas(10,28). The incidence of tuberculosis was higher in those cases with protein levels higher than 4 g/ dL in t he presen t st u dy. This fin din g has been considered suggestive of effusion due to infection(3,5). However, there was no increase in the specificity of ADA levels when it was combined with protein levels higher than 4 g/dL, probably due to the fact that empyema was present in 9 of the 10 false- positive diagnoses.
The presen ce of pleu ral effu sion in you n g adu lt s is su g g est ive o f a t u b ercu lo u s et io lo g y, esp ecially in t h o se reg io n s wh ere t h ere is h ig h p revalen ce o f t h e d isease. Th ere was n o in crease in sp ecificit y o f ADA d et erm in at io n in t h e g ro u p o f p at ien t s yo u n g e r t h a n 4 5 b e ca u se t h e re we re se ve ra l pat ien t s who presen t ed wit h em pyem a at t his age. Th is h as also b een rep o rt ed in o t h er st u d ies(11 ,1 9 ,4 2 ). Th e co m b in at io n o f t h ese p aram et ers h as b een reco m m en d ed in m ed ica l p ra ct ice in o rd er t o in crea se efficien cy in t h e d ia g n o sis o f p leu ra l t u b e r c u lo s is(1 0 , 1 8 , 1 9 , 4 3 ) s in c e it in c r e a s e s t h e p ro b ab ilit y o f d iag n o sis p rio r t o o t h er t est s, an d sin ce em p yem a can b e easily d iag n o sed t h ro u g h m acro sco p ic evalu at io n o f t h e p leu ral flu id .
When we choose t he crit erion t hat on e t est or an other shou ld be positive, the likelihood of makin g an accu rate diagn osis will vary, in creasin g sensitivity at t he expense of specificit y. When we decide t hat bot h t est s shou ld be posit ive, a correct diagn osis is more likely t o be achieved. Un less bot h t est s are very sen sit ive, specificit y in creases an d sen sit ivit y decreases in t he lat t er case(4 4 ).
Currently, diagnostic tests may represent the best mean s of con servin g healt h care resou rces. Rapid and accurate tests are essential for effective treatment and cost reduction. Determining ADA levels is simple, rapid, inexpensive and easily performed. This method can be widely u sed, especially in poor areas. There are n o addit ion al risks, sin ce it is performed u sin g flu id obt ain ed du rin g t horacocen t esis, a rou t in e procedu re in t he in vest igat ion of all cases of pleu ral effusion. We suggest that ADA testing be adopted as a rou t in e procedu re in medical pract ice sin ce t here is mu ch con sist en t eviden ce of it s u sefu ln ess.
REFERENCES
1 . Neves DD. O valor da adenosina desaminase no diagnóstico diferen cial dos derrames pleu rais [Tese de Mest rado]. Rio de Janeiro: Universidade Federal do Rio de Janeiro; 1992. 2 . Si l va J r CT. Ad e n o s i n a d e s a m i n a s e “ ve r s u s ” h ist o p a t o ló g ico p le u ra l: a va lia çã o d a im p o rt â n cia d a t o r a c o c e n t e s e i s o l a d a p a r a o d i a g n ó s t i c o d a t u b ercu lo se p leu ra l [Tese d e d o u t o ra d o ]. Nit eró i (RJ ): Un iversid a d e Fed era l Flu m in en se; 2 0 0 0 .
3 . Ma rt in s SAS, Gerh a rd t Filh o G, Sa n t ia g o AC, Peyn ea u AR, Pa iva HC, Gu im a rã e s CA, De t t o n i VV. De rra m e p le u ra l t u b e rcu lo so . Tisio - Pn e u 1 9 7 7 ; IX(1 ): 1 3 3 - 6 6 . 4 . Seib ert AF, Ha yn es J r J , Mid d let o n R, Ba s J B. Tu b ercu lo u s
p le u r a l e f f u s io n - t w e n t y- ye a r e x p e r ie n c e . Ch e s t 1 9 91 ; 9 9 : 8 8 3 - 6 .
5 . Lig h t RW. Pleu ra l Disea ses. 3 rd ed . Ph ila d elp h ia : Lea & Fe b ig e r; 1 9 9 5 .
6 . Ferrer J , Ha m m H, Lig h t RW. Pleu ra l t u b ercu lo sis. Eu r Resp ir J 1 9 9 7 ;1 0 :9 4 2 - 7 .
7 . Valdes L, Alvarez D, San Jose E, Penela P, Valle JM Garcia-Pazos JM, Suarez J, Pose A. Tuberculous pleurisy: a study of 254 pat ien t s. Arch In t ern Med 1998;158(18):2017- 21. 8 . Fo lla d o r ECR, Pim e n t e l M, Ba rb a s CSV, Ta ka g a ki TY, Ka ira lla RA, Deh ein zelin D, Ba rb a s Filh o J V. Derra m e p le u ra l t u b e rcu lo so : a va lia ca o clin ica e la b o ra t o ria l. Rev Ho sp Clin Fa c Med Sa o Pa u lo 1 9 91 ;4 6 (4 ):1 7 6 - 9 . 9 . So a res ECC. Sist em a Na cio n a l d e Ag ra vo s d e No t ifica çã o
(SIN AN ): In f o r m a ç õ e s s o b r e a s n o t i f i c a ç õ e s d e t u b e rcu lo se o b t id a s n a SMS- RJ . In . Rio d e J a n e iro : Secret a ria Mu n icip a l d e Sa ú d e; 2 0 0 2 .
1 9 9 3 ; 1 0 3 (2 ): 4 5 8 - 6 5 .
1 3 . Ch a lh o u b M, Cru z AA, Ma rcilio C, Net t o MB. Va lo r d a d e t e rm in a çã o d a a t ivid a d e d a a d e n o sin a d e sa m in a se (ADA) n o d ia g n ó st ico d iferen cia l d o s d erra m es p leu ra is. Rev Asso c Med Bra s 1 9 9 6 ;4 2 (3 ):1 3 9 - 4 6 .
1 4 . En a J , Va llis V, Ot eyza CP, Sa la m a n ca RE. Ut ilid a d y l i m i t a c i o n e s d e l a a d e n o s i n a d e s a m i n a s a e n e l d i a g n ó s t i c o d e l a p l e u r e s í a t u b e r c u l o s a . Es t u d o m et a a n a lít ico . Med Clin (Ba rc) 1 9 9 0 ; 9 5 : 3 3 3 - 5 . 1 5 . I Co n s e n s o Br a s ile ir o d e Tu b e r c u lo s e . So c ie d a d e
Bra sile ira d e P n e u m o lo g ia e Tisio lo g ia . J P n e u m o l 1 9 9 7 ; 2 3 (6 ): 2 81 - 3 4 2 .
1 6 . Ka t a ria YP. Ad en o sin e d ea m in a se in t h e d ia g n o sis o f t u b ercu lo u s p leu ral effusio n . Ch est 2 0 01 ;1 2 0 (2 ):3 3 4 - 5 . 1 7 . Pé re z - Ro d rig u e z E, Ca st ro DJ . Th e u se o f a d e n o sin e d ea m in a se a n d a d en o sin e d ea m in a se iso en zym es in t h e d ia g n o sis o f t u b ercu lo u s p leu rit is. Cu rr Op in Pu lm Med 2 0 0 0 ; 6 : 2 5 9 - 6 6 .
1 8 . Ville g a s MV, La b ra d a LA, Sa ra via NG. Eva lu a t io n o f p o lym era se ch a in rea ct io n , a d en o sin e d ea m in a se a n d in t erferon - g in pleu ral flu id for t he diferen t ial diagn osis o f p leu ral t u b ercu lo sis. Ch est 2 0 0 0 ;11 8 (5 ):1 3 5 5 - 6 4 . 1 9 . Va ld es L, Alva rez D, Sa n J o sé E, J u a n a t ey J R, Po se A,
Va lle J M, Sa lg u eiro M, Su a rez J R. Va lu e o f a d en o sin e d e a m in a se in t h e d ia g n o sis o f t u b e rc u lo u s p le u ra l e f f u s io n s in yo u n g p a t ie n t s in a r e g io n o f h ig h p reva len ce o f t u b ercu lo sis. Th o ra x 1 9 9 5 ; 5 0 : 6 0 0 - 3 . 2 0 . Light RW, Macgregor MI, Luchsinger PC, Ball WC Jr. Pleural
effu sio n s: Th e d iag n o sis sep arat io n o f t ran su d at es an d exsu dat es. Am In t Med 1972;77(4):507- 13.
2 1 . Ma rel M, St a st n y B, Milin ová L, Sva n d ová E, Lig t h RW. Dia g n o sis o f p leu ra l effu sio n s. Exp erien ce wit h clin ica l st u d ies, 1 9 8 6 t o 1 9 9 0 . Ch est 1 9 9 5 ; 1 0 7 : 1 5 9 8 - 6 0 3 . 2 2 . Chaulhoub M, Fidelis R, Barreto AP, Ramos E, Barral- Netto
M, Barbosa Jr AA. Impacto de múltiplas biópsias em dois pon t os dist in t os da su perfície pleu ral n o diagn óst ico de t u bercu lose. J Pn eu mol 2000;26(2):55- 60.
2 3 . Ch a lh o u b M, Arru d a S, Fid élis R, Ba rret o AP, Ba rra l Net o M. An á lise d a b ió p sia p le u ra l e m 1 0 7 p a cie n t e s se m líq u id o p leu ra l. J Pn eu m o l 1 9 9 9 ; 2 5 (3 ): 1 41 - 6 . 2 4 . Hirsch A, Ru ffie P, Nebu t M, Bign on J , Chrét ien J . Pleu ral
e f f u s io n : la b o r a t o r y t e s t s in 3 0 0 c a s e s . Th o r a x 1 9 7 9 ; 3 4 : 1 0 6 - 1 2 .
2 5 . Lig h t RW. P le u ra l e f f u s io n s . M e d Clin No r t h Am 1 9 7 7 ; 61 (6 ): 1 3 3 9 - 5 2 .
2 6 . Giust i G. Aden osin e deam in ase. In : Bergm eyer HU, edit or. Met h o d s o f En zym a t ic An a lysis. New Yo rk: Aca d em ic Press; 1 9 7 4 . p . 1 0 9 3 - 9 .
2 7 . Do n a t h J . Fro m t h e m a g ic m o u n t a in t o m o d ern t im es. Ch e st 1 9 9 7 ; 111 (5 ): 11 5 3 - 4 .
2 8 . Kim YC, Pak KO, Bom HS, Lim SC, Na HJ, Park JH. Combining ADA, protein and IFN- gamma best allow a discrimination
Salazar- Lezama M. Adenosine deaminase in the diagnosis of tuberculous pleural effusions: a report of 218 patients an d review of t he lit erat u re. Chest 1991;99(2):355- 7. 3 2 . Ma rit z FJ , Ma la n C, Ro u x I. Ad e n o s in e d e a m in a s e
est im a t io n s in t h e d ifferen t ia t io n o f p leu ra l effu sio n s. S Afr Med J 1 9 8 2 ;6 2 :5 5 6 - 8 .
3 3 . Oca ñ a I, Ma rt in Vá zq u ez J M, Seg u ra RM, Fern a n d ez-d e - Se villa T, Ca p ez-d e vila J S. Aez-d e n o sin e ez-d e a m in a se in p leu ra l flu id s: a t est fo r d ia g n o sis o f t u b ercu lo sis p leu ra l e ffu sio n s. Ch e st 1 9 8 3 ; 8 4 (1 ): 51 - 3 .
3 4 . Perez d e Ot eyza C, Ch a n t res MT, Reb o lla r J L, Mu n o z Ya n ez MC, Ga rcia Ma rco s F, Perez Ba rb a M, En riq u ez d e Sa la m a n ca R. Ad en o sin e d ea m in a se in p leu ra l effu sio n s. It ’s u sefu ln ess in t h e d ia g n o sis o f t u b ercu lo us p leu risy. An n Med In t ern a l 1 9 8 9 ;6 (5 ):2 4 4 - 8 .
3 5 . Pet t ersson T, Ojala K, Weber TM. Aden osin e deam in ase in t h e d ia g n o sis o f p leu ra l effu sio n s. Act a Med Sca n d 1 9 8 4 ; 2 1 5 : 2 9 9 - 3 0 4 .
3 6 . Bu rg ess LJ , Ma rit z FJ , Ro u x I, Ta lja a rd J J F. Co m b in ed u se o f p leu ra l a d en o sin e d ea m in a se wit h lym p h o cyt e/ n eu t ro p h il ra t io . In crea sed sp ecificit y fo r t h e d ia g n o sis o f t u b e rcu lo u s p le u rit is. Ch e st 1 9 9 6 ; 10 9 (2 ): 41 4 - 9 . 3 7 . Neves DD, Preza PCA, Dias RM, Carvalho SRS, Chibante AMS,
Silva Jr CT, Aidê MA. Comparative study between interferon-gamma and adenosine deaminase in the diagnosis of pleural effu sion in a high prevalen ce area of t u bercu losis. Am J Respir Crit Care Med 1999;159(3 part 2):A555.
3 8 . Bo t t in i P V, Alve s- Cu n h a FA, So u z a MI, Ga rlip p CR. Lym p h o cyt ic p leu ra l effu sio n s: d ia g n o st ic a p p lica t io n o f a d e n o s i n e d e a m i n a s e a c t i v i t y. J Br a s P a t o l 1 9 9 6 ; 3 2 (4 ): 1 4 6 - 5 2 .
3 9 . J a y SJ . Dia g n o sis p ro ce d u re s fo r p le u ra l d ise a se . In Sym p o siu m o n p le u ra l d ise a se s. Clin Ch e st Me d 1985;6(1):33- 48.
4 0 . Me st it z P, Po lla n d AC. Th e d ia g n o sis o f t u b e rcu lo u s p leu ra l effu sio n . Brit J Dis Ch est 1 9 5 9 ;5 3 :8 6 - 9 4 . 41 . Ocaña I, Martinez- Vázquez JM, Ribera E, Segura RM, Pascual
C. Ad e n o sin e d e a m in a se a ct ivit y in t h e d ia g n o sis o f lym phocyt ic pleu ral effu sion s of t u bercu lou s, n eoplast ic an d lymphomat ous origin . Tu bercle 1986;67:141- 5. 4 2 . Ga rcía Ló p e z MP, Sa la z a r Le z a m a MA. Et io lo g ía d e l
d e r r a m e p l e u r a l e n e l In s t i t u t o N a c i o n a l d e En ferm ed a d es Resp ira t o ria s. Rev In st Na c En ferm ed a d es Re sp ir 1 9 9 9 ; 1 2 (2 ): 9 7 - 1 0 0 .
4 3 . Ha m a d a T, Sa n a ka M, Ha t a E, Ha se g a wa T. [Ple u ra l a d en o sin e d ea m in a se levels in t u b ercu lo u s p leu risy—it s d iag n o st ic p erfo rm an ce u n d er t h e d ifferen t p revalen ces in t h e d iffe re n t a g e o f p o p u la t io n ] [a b st ra ct ]. J p n J Th o ra c Ca rd iova sc Su rg 1 9 9 8 ;4 6 (1 ):51 - 7 .
