INT J TUBERC LUNG DIS 14(11):13821387
2010 The Union
Diagnostic value of adenosine deaminase in cerebrospinal
uid for tuberculous meningitis: a meta-analysis
H-B. Xu,* R-H. Jiang, L. Li,* W. Sha, H-P. Xiao
* Department of Clinical Pharmacy, Shanghai Tenth Peoples Hospital, Tongji University School of Medicine, Shanghai,
Department of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
O B J E C T I V E : To determine the accuracy of adenosine
deaminase (ADA) measurements in the diagnosis of tu-
berculous meningitis (TBM).
D E S I G N : After a systematic review of English language
studies, the sensitivity, specificity and accuracy of ADA
concentrations in the diagnosis of cerebrospinal fluid
(CSF) were evaluated using random effects models. Sum-
mary receiver operating characteristic curves were used
to summarise overall test performance.
R E S U LT S : Ten studies met our inclusion criteria. The
TUBERCULOSIS (TB) is a major cause of morbidity
and mortality, the global incidence of which is increas-
ing by 0.4% per annum.1 Tuberculous meningitis
(TBM) is one of the most harmful infectious diseases,
and accounts for 1% of all forms of TB. About 30%
of TBM patients die despite anti-tuberculosis chemo-
therapy, and early institution of treatment is essential
for satisfactory improvement.2,3 The diagnosis of TBM
is difficult due to the low sensitivity of acid-fast ba-
cilli (AFB) microscopy using Ziehl-Neelsen staining
of the cerebrospinal fluid (CSF), and defining the
growth of Mycobacterium tuberculosis bacilli is time
consuming.4,5 A quick, non-invasive test to confirm
TBM would therefore be helpful.
Adenosine deaminase (ADA) is an enzyme widely
distributed in tissues and body fluid used in the diag-
nosis of TB in pleural, meningeal and pericardial flu-
ids.6 The measurement of ADA was initiated by Giusti
in 1981 and applied extensively in clinical practice.7
Although its use has become popular in many coun-
tries, there is no consensus regarding its current use-
fulness in clinical practice.
We performed a systematic review of the literature
and a meta-analysis to determine the usefulness of
ADA measurement in the diagnosis of TBM.
MATERIALS AND METHODS
Search strategy and study selection
As the present study was a meta-analysis based on
published articles, we did not require patient consent
Correspondence to: L Li, Department of Clinical Pharmacy, Shanghai Tenth Peoples Hospital, Tongji University School of
Medicine, Shanghai, China. Tel: (+86) 216 630 2761. Fax: (+86) 216 630 7668. e-mail: jiangruihua119@yahoo.cn
REVIEW ARTICLE
SUMMARY
sensitivity of ADA in the diagnosis of TBM was 0.79
(95%CI 0.750.83), specificity 0.91 (95%CI 0.890.93),
positive likelihood ratio 6.85 (95%CI 4.1111.41), neg-
ative likelihood ratio 0.29 (95%CI 0.190.44) and diag-
nostic odds ratio 26.93 (95%CI 12.7356.97).
C O N C L U S I O N : Our data suggest that ADA in the CSF
can be a sensitive and specific target and a critical crite-
ria for the diagnosis of TBM.
K E Y W O R D S : adenosine deaminase; cerebrospinal fluid;
tuberculosis
or the approval of institutional review boards. We
searched the following electronic databases: Med-
line (19662009), Embase (19802009), Web of Sci-
ence (19902009), BIOSIS (19942009) and LILACS
(19802009). All searches were up to date as of May
2009. The search terms used included tuberculosis,
Mycobacterium tuberculosis, meningitic/meningi-
tis, cerebrospinal effusion/cerebrospinal fluid, ade-
nosine deaminase/ADA, sensitivity and specificity
and accuracy. We contacted experts in the speciality
and searched reference lists from primary and review
articles. Articles published in English were reviewed
and analysed, while conference abstracts and letters
to journal editors were excluded due to their limited
data content.
Studies were included in the present meta-analysis
if they provided both the sensitivity (true-positive rate)
and the specificity (false-positive rate) of ADA in the
diagnosis of TBM, or if they provided ADA values in a
dot-plot form, allowing test results to be extracted for
individual study subjects. As very small studies may
be vulnerable to selection bias, only studies including
at least 10 TBM specimens were selected for inclusion
in the study. Two reviewers (HBX and RHJ) indepen-
dently judged study eligibility while screening the ci-
tations. Disagreements were resolved by consensus.
Data extraction and quality assessment
The final set of English language articles was assessed
independently by two reviewers (HBX and RHJ). The
reviewers were blinded to publication details, and
 Diagnostic value of ADA for TBM 1383

Table 1 Summary of studies included

Test results Quality score

Patients Cut-off
Study, year, reference n Assay method IU/l TP FP FN TN STARD QUADAS
Chotmongkol, 20068 177 Giusti method 15.5 12 11 4 42 9 7
Kashyap, 20079 153 Giusti method 5 55 12 11 75 14 9
Lopez-Cortes, 199510 180 Kinetic determination 10 10 11 10 149 12 7
Corral, 200411 62 Spectrophotometric method 8.5 8 6 6 42 15 10
Kashyap, 200612 281 Giusti method 11.39 96 10 21 154 13 10
Mishra, 199513 35 Giusti method 5 24 3 3 5 11 9
Choi, 200214 182 Giusti method 10 21 6 15 140 15 11
Rohani, 199515 119 Giusti method 9 14 13 0 92 13 8
Ribera, 198716 205 Giusti method 9 32 2 0 171 9 8
Coovadia, 198617 78 Giusti method 10 11 18 4 45 13 11
IU = international unit; TP = true-positive; FP = false-positive; FN = false-negative; TN = true-negative; STARD = standards for reporting diagnostic accuracy;
QUADAS = quality assessment for studies of diagnostic accuracy.

disagreements were resolved by consensus. Data re-
trieved from the reports included participant charac-
teristics, test methods, sensitivity and specificity data,
cut-off values, publication year and methodological
quality. The numbers of true-positive, false-positive,
false-negative and true-negative results are shown in
Table 1.
We assessed the methodological quality of the
studies using guidelines published by the standards
for reporting diagnostic accuracy (STARD) initiative
(maximum score 25) and the quality assessment for
studies of diagnostic accuracy (QUADAS) tool (max-
imum score 14).18,19 In addition, for each study the
following study design characteristics were also re-
trieved: 1) cross-sectional design (vs. case-control de-
sign), 2) consecutive or random sampling of patients,
3) blinded (single or double) interpretation of deter-
mination and reference standard results, and 4) pro-
spective data collection. If no data on the above crite-
ria were reported in the primary studies, we requested
the information from the authors. If the authors did
not respond to our letters, the unknown items were
treated as no.
Statistical analysis
The kappa () coefficient was calculated as a measure
of agreement between two reviewers. We used stan-
dard methods recommended for meta-analyses of di-
agnostic test evaluations.20 The following measures
of test accuracy for each study, e.g., sensitivity, speci-
ficity, positive likelihood ratio (PLR), negative likeli-
hood ratio (NLR) and diagnostic odds ratio (DOR)
were computed using several statistical software pro-
grammes. The analysis was based on a summary re-
ceiver operating characteristic (SROC) curve.20,21 The
sensitivity and specificity for the single test threshold
identified for each study were used to plot an SROC
curve.21 A random effects model was used to cal-
culate the average sensitivity, specificity and other
measures across studies.22 The term heterogeneity
when used in relation to meta-analyses refers to the
degree of variability. Fishers exact tests were used to
detect significant heterogeneity. To assess the effects of
STARD and QUADAS scores on the diagnostic values
of ADA, we included them as covariates in univariate
meta-regression analysis (inverse variance weighted).
We also analysed the effects of other covariates on
DOR (i.e., cross-sectional design, consecutive or ran-
dom sampling of patients, single or double interpre-
tation of determination and reference standard re-
sults, and prospective data collection). The relative
DOR (RDOR) was calculated to analyse the change
in diagnostic precision in the study per unit increase
in the covariate.23 As publication bias is a risk in
meta-analyses of diagnostic studies, we tested the po-
tential presence of this bias using the Egger test.24
RESULTS
After independent review, 16 publications dealing
with ADA concentrations for the diagnosis of TBM
were considered to be eligible for inclusion in the anal-
ysis.814,2530 Studies were excluded if ADA concen-
tration was determined only in TBM patients,30 they
recruited <10 patients with confirmed TBM,26 or
they did not calculate the sensitivity or specificity.25,27,29
Some of the data might reappear in the publication.13,28
A final 10 studies817 involving 375 patients with TBM
and 989 non-TBM patients were available for analy-
sis; the clinical characteristics of these studies, along
with their QUADAS scores, are outlined in Table 1.
Quality of reporting and study characteristics
The average internal agreement between the two re-
viewers for items in the quality checklist was 0.9. The
average sample size of the included studies was 136
(range 35281). In all 10 studies,817 the diagnoses of
all patients with TBM were made based on positive
smears or cultures of M. tuberculosis in the CSF and/
or on clinical symptoms. There were also increased
proteins, decreased glucose and good response to anti-
tuberculosis drugs in the CSF. Our initial data were
affected by the poor quality of reporting in the pri-
mary studies. To overcome this problem, we contacted
all authors of the 10 studies by airmail as well as
e-mail where e-mail addresses were available. Six
1384 The International Journal of Tuberculosis and Lung Disease

Table 2 Characteristics of included studies

TB patients/ Reference Cross-sectional Consecutive Blinded

Study, year, reference non-TB subjects standard design or random design Prospective
Chotmongkol, 20068 15/53 Bac /clin Yes Yes No Yes
Kashyap, 20079 66/87 Bac /clin Yes Yes No Yes
Lopez-Cortes, 199510 20/160 Bac /clin Yes Yes Yes Yes
Corral, 200411 14/48 Bac No Yes No No
Kashyap, 200612 117/164 Bac /clin Yes Yes No Yes
Mishra, 199513 27/84 Bac /clin No Unknown No Yes
Choi, 200214 36/146 Bac /clin Yes Yes No No
Rohani, 199515 14/105 Bac /clin Unknown Yes Unknown Yes
Ribera, 198716 32/173 Bac Unknown Yes No Yes
Coovadia, 198617 15/63 Bac /clin Unknown Unknown Unknown Yes
TB = tuberculosis; bac = bacteriology; clin = clinical course.

authors responded who could provide additional
data.812,14 As shown in Table 2, 5 of the 10 studies
(50%) were cross-sectional in design. In eight studies
(80%), the samples were collected from consecutive
patients. Eight studies (80%) were prospective.
Diagnostic accuracy
Figure 1 shows the forest plot of sensitivity and speci-
ficity of the 10 ADA assays in the diagnosis of TBM.
Sensitivity and specificity ranged from 0.50 to 1.00
A thresholds on sensitivity and specificity in a single
(mean 0.79, 95% confidence interval [CI] 0.750.83)
and from 0.63 to 0.99 (mean 0.91, 95%CI 0.89
0.93), respectively. PLR was 6.85 (95%CI 4.1111.41),
NLR 0.29 (95%CI 0.190.44) and DOR 26.92
(95%CI 12.7256.97). 2 values of sensitivity, speci-
ficity, PLR, NLR and DOR were respectively 44.80
(P < 0.001), 63.60 (P < 0.001), 51.66 (P < 0.001),
34.82 (P < 0.001) and 29.75 (P < 0.001), indicating
significant heterogeneity for sensitivity, specificity,
PLR, NLR and DOR between the studies.
Unlike a traditional receiver operating character-
istic (ROC) plot that explores the effect of varying
study, each data point in the summary ROC (SROC)
plot represents a separate study. The SROC curve
presents a global summary of test performance and
shows the trade-off between sensitivity and specificity.
A graph of the SROC curve for the ADA determina-
tion showing true-positive vs. false-positive rates from
individual studies is shown in Figure 2. As a global
measure of test efficacy we used the Q-value, the in-
tersection point of the SROC curve with a diagonal
line from the left upper corner to the right lower

Figure 1 Forest plot of estimate of sensitivity (A) and specic-
ity (B) for adenosine deaminase assays in the diagnosis of TBM.
Circles = point estimates from each study; error bars = 95%CIs.
Pooled estimate of sensitivity for adenosine deaminase assays
was 0.79 (95%CI 0.750.83); pooled estimate of specicity
was 0.91 (95% CI 0.890.93). TBM = tuberculous meningitis;
CI = condence interval.
Figure 2 SROC curves for adenosine deaminase assays.
Circles = each study in the meta-analysis (the size of each
study is indicated by the size of the solid circle); the maximum
joint sensitivity and specicity (i.e., the Q value) was 0.85; the
area under the curve was 0.9154. SROC curves summarise
overall diagnostic accuracy. SROC = summary receiver operat-
ing characteristic.

Table 3 Weighted meta-regression of the effects of methodological quality and study design
on diagnostic precision of cerebrospinal adenosine deaminase in 10 assays
Studies
Covariates n Coefcient
STARD 13 6 0.168
QUADAS 10 4 0.137
Cross-sectional design 5 0.427
Consecutive or random 8 2.243
Blinded 2 0.411
Prospective 8 0.231
RDOR = relative diagnostic odds ratio; STARD = standards for reporting diagnostic accuracy; QUADAS = quality
assessment for studies of diagnostic accuracy.
corner of the ROC space, which corresponds to the
highest common value of sensitivity and specificity
for the test. This point does not indicate the only or
even the best combination of sensitivity and specific-
ity for a particular clinical setting, but represents an
overall measure of the discriminatory power of a test.
Our data showed that the SROC curve was positioned
near the desirable upper left corner of the SROC curve,
and the Q value was 0.85, while the area under the
curve (AUC) was 0.92, indicating a high level of over-
all accuracy.
Multiple regression analysis and publication bias
Using STARD guidelines, a quality score for every
study was compiled on the basis of the title, intro-
duction, methods, results and discussion (Table 1).18
Quality was scored using QUADAS, where 1, 0 or
1 were given if all criteria were fulfilled, unclear or
not achieved, respectively (Table 1).19 These scores
were used in the meta-regression analysis to assess
the effect of study quality on the RDOR of ADA in
the diagnosis of TBM. As shown in Table 3, there was
Figure 3 Funnel graph for the assessment of potential publi-
cation bias in adenosine deaminase assays. The funnel graph
plots the log of the OR against the SE of the log of the OR (an
indicator of sample size). Circles = each study in the meta-
analysis. The result of the Egger test for publication bias was not
signicant (P = 0.171). OR = odds ratio; SE = standard error.
Diagnostic value of ADA for TBM 1385
RDOR P value
0.84 (0.441.63) 0.5628
0.87 (0.391.97) 0.7041
1.53 (0.337.10) 0.5316
9.42 (0.61144.42) 0.0932
0.66 (0.133.39) 0.5702
1.26 (0.236.87) 0.7565
no statistical significance in RDOR values between
studies of higher (STARD score 13, QUADAS score
10) and lower quality. There was no significant dif-
ference between studies that were or were not blinded,
cross-sectional, consecutive/random and prospective.
The evaluation of publication bias showed that the
Egger test was not significant (P = 0.171). The funnel
plots for publication bias (Figure 3) also did not show
any asymmetry. These results indicate a lack of po-
tential for publication bias.
DISCUSSION
Making a differential diagnosis between TBM and
non-TBM is a critical clinical problem. Conventional
methods, such as the direct examination of CSF, are
positive in only 5~20% of cases. The rate of positivity
is about 40% in culture, which takes about 6 weeks.4,5
Cerebrospinal levels of some biomarkers have been
proposed to be helpful in the diagnosis of TBM, in-
cluding ADA. The present meta-analysis shows that
the mean values of the sensitivity and specificity of the
ADA assays were respectively 0.79 and 0.91, and that
the maximum joint sensitivity and specificity (Q value)
was 0.85, while the AUC was 0.92, indicating a high
level of overall accuracy. We also noted that three
studies16,29,32 showed relatively low sensitivity (<0.70)
and six studies15,28,29,31 demonstrated low specificity
(<0.90) for the detection of ADA in diagnosing TBM.
DOR is a single indicator of test accuracy that
combines the data from sensitivity and specificity
into a single number and the ratio of the odds of posi-
tive test results in the patient with disease or without
disease.31 DOR values range from 0 to infinity, with
higher values indicating better discriminatory test per-
formance (i.e., higher accuracy). In the present meta-
analysis, we found that the mean DOR was 26.92,
also indicating a high level of overall accuracy, and
also presented both PLR and NLR as diagnostic ac-
curacy, as the SROC curve and the DOR are not easy
to interpret and use in clinical practice, and ratios are
considered to be more clinically meaningful.32,33 A
PLR of 6.85 suggests that TBM patients have an
approximately 7-fold higher chance of being ADA
assay-positive as compared to patients without TBM.
However, if the ADA assay result is negative, the
1386 The International Journal of Tuberculosis and Lung Disease
probability that the patient has TBM is approximately
29%, which is not low enough to rule out TBM. These
data suggest that a negative ADA assay result should
not be used alone as a justification to exclude or dis-
continue anti-tuberculosis treatment. The choice of
therapeutic strategy should be based on the results of
microscopic examination of a smear or culture for
M. tuberculosis, as well as other clinical data, such as
response to anti-tuberculosis treatment.
An exploration of the reasons for heterogeneity
rather than the computation of a single summary mea-
sure is an important goal of meta-analysis.34 In our
meta-analysis, both STARD and QUADAS scores were
used to assess the effect of study quality on RDOR. We
found significant heterogeneity for sensitivity, speci-
ficity, PLR, NLR, and DOR among the studies anal-
ysed, although the exact mechanism responsible for
the significance was inexplicable. There were no dif-
ferences between studies with or without blinded,
cross-sectional, consecutive/random and prospective
design, which may contribute to the quality of the
test performance.
Publication bias may also have been introduced by
the inflation of diagnostic accuracy estimates, as stud-
ies with positive results were more likely to be ac-
cepted for publication. TBM is not always diagnosed
by microbiological examination. The heterogeneity
detected in the present analysis may have limitations.
TBM was diagnosed in some patients with TBM only
on clinical course. This can cause non-random mis-
classification, leading to biased results.
In conclusion, current evidence suggests a poten-
tial role of ADA assays in confirming a diagnosis of
TBM. There is a great need to develop CSF biomark-
ers specific for TBM. The results of ADA assays
should be interpreted with clinical findings and other
examinations.
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O B J E C T I F : Dterminer la prcision des mesures de lade-
nosine deaminase (ADA) dans le diagnostic de la mnin-
gite tuberculeuse (TBM).
S C H M A : Aprs une revue systmatique des tudes en
langue anglaise, la sensibilit, la spcificit et la prcision
des concentrations de lADA pour le diagnostic dans le
liquide crbrospinal (CSF) ont fait lobjet dune valua-
tion par les modles deffets alatoires. On a utilis les
courbes sommaires dopration du receveur pour rsu-
mer les performances globales du test.
R S U LTAT S : Dix tudes ont rpondu nos critres din-
O B J E T I V O : Determinar la exactitud de las mediciones
de desaminasa de adenosina (ADA) en el diagnstico de
la meningitis tuberculosa (TBM).
M T O D O : Despus de un anlisis sistemtico de las
publicaciones cientficas en ingls, se evalu la sensibili-
dad, la especificidad y la exactitud de las concentracio-
nes del ADA del liquido cefalo-rachidiano (CSF) en el
diagnstico de la TBM mediante modelos de efectos
aleatorios. La eficacia global de la prueba se valid con
curvas de resumen de rendimiento diagnstico.
R E S U LTA D O S : Diez estudios cumplieron con los crite-
Diagnostic value of ADA for TBM 1387
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ratio: a single indicator of test performance. J Clin Epidemiol
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RSUM
clusion. La sensibilit de lADA pour le diagnostic de
la TBM a t de 0,79 (IC95% 0,750,83), sa spcificit
de 0,91 (IC95% 0,890,93), le ratio de vraisemblance
positive de 6,85 (IC95% 4,1111,41), le ratio de vrai-
semblance ngative de 0,29 (IC95% 0,190,44) et le
coefficient (rapport) de diagnostic de 26,93 (IC95%
12,7356,97).
C O N C L U S I O N : Nos donnes suggrent que lADA du
CSF peut tre une cible sensible et spcifique et un critre
critique pour le diagnostic de la TBM.
RESUMEN
rios de inclusin. La sensibilidad de la concentracin del
ADA en el diagnstico de TBM fue 0,79 (IC95% 0,75
0,83), la especificidad fue 0,91 (IC95% 0,890,93), el
cociente de verosimilitud positivo fue 6,85 (IC95%
4,1111,41), el cociente de verosimilitud negativo fue
0,29 (IC95% 0,190,44) y el cociente de posibilidades
diagnsticas fue 26,93 (IC95% 12,7356,97).
C O N C L U S I N : Los datos obtenidos indican que la con-
centracin del ADA del CSF puede ser una variable sen-
sible y especfica y un criterio esencial en el diagnstico
de la TBM.