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Diagnostic Value of Adenosine Deaminase (ADA)

in Ascitic Fluid for Peritoneal Tuberculosis:

an Evidence-based Case Report

Author : dr. Juliyanti

Chief of Ward: dr. Mulia

Supervisor: dr. Nadia Ayu Mulansari, SpPD


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Introduction

Tuberculosis causes some 2 million deaths per year world wideand is increasing in incidence in developed and developingcountries.

The peritoneum is the sixth most common extra pulmonary site.

The reported incidence of peritoneal TB among all forms of TBvaries from 0.1% to 0.7% worldwideand it can be expected to

increase with the increasing incidence of TB worldwide.


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Peritoneal tuberculosis

Usually results from the reactivation of latent TB in peritoneal focithat were established after hematogenous spread from a primarylung focus.

Manifested as ascites of insidious onset, abdominal pain and fever.

The non-specific symptoms associated with PTB and its challengingclinical course can interfere with a definitive diagnosis, and TBperitonitis is often confused with other intra-abdominal diseases.

Delayed diagnosis increases the morbidity and mortality of PTB.


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Diagnosis of PTB

Diagnostic tests for PTB are difficult and time-consuming because

of paucity of M. tuberculosis in peritoneal fluid.

It requires histological confirmation of caseous granulomas or

bacteriological confirmation, by using ascitic fluid-derived acid-

fast bacilli (AFB) smears as well as cultures for M. tuberculosis.

Cultures for M. tuberculosis require 4 weeks and AFB smears aretoo insensitive to meet current needs.

A laparoscopy-guided biopsy can be used to obtain a rapid

diagnosis of PTB; however it is associated with risks related toanesthesia and potential injury and bleeding.


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Adenosine deaminase (ADA)

ADA is a purine-degrading enzyme that catalyses thedeamination of adenosine, resulting in the production of inosine

ADA is widely distributed in tissues and body fluids, and its levelscan be used to differentiate T cells from B cells; ADA levels are

1012 times higher in T cells than in B cells; its level vary with theproliferative status and the maturity of cells.

ADA is increased in tuberculous ascitic fluid because of thestimulation of T cells by the mycobacterial antigens. Its levels in

body fluids can be measured rapidly, provide an alternative forthe diagnosis of TB.


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Case resume

Female, 51 years old, with chief complaint of progressiveabdominal swelling since 2 months prior to admission.

She had abdominal pain occasionally, malaise, anorexia andweight loss but had no history of night sweat or fever.

She had no history of prior liver disease or alcoholic abuse,denied symptoms of dyspnea, cough, chest pain or legswelling

She was diagnosed with diabetes mellitus and hypertensionsince 3 years before and was regularly on lisinopril and

metformin. She was non-smoker, menopause 6 years ago and had no

complaint of vaginal bleeding.


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Case resume (2)

Physical examination revealed normal vital sign, dullness

on percussion of left lower thorax with decreased breath

sound, positive shifting dullness on abdomen, no

stigmata of hepatic cirrhosis and no peripheral edema.

Laboratory result showed leukocytosis, thrombocytosis,

elevated ESR, moderate hyponatremia, hyperglycemia,

normal kidney and liver function test, elevated CA 125

level (537 U/mL), normal albumin and increased globulin.

Serological test for HIV, hepatitis B and C were negative.Fecal and urine analysis were normal


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Case resume (3)

Chest x-ray revealed left sided pleural effusion with nosign of parenchymal involvement. Abdominal ultrasoundsshowed free peritoneal fluid with no significant finding inabdominal viscera. An abdominal CT scan showedabundant free fluid but no other sign of abnormality.

Gynecological study revealed normal result exceptadhesive fibrin on ascitic fluid.

A diagnostic paracentesis was carried out, and a clearyellowish ascitic fluid was obtained that contained 1650cells/ul, 99.9 % of which were mononuclear cells

(lymphocyte). LDH was very high, proteins wereincreased, serum-asites albumin gradient was < 1,1 g/dl(0,5 g/dl) and A Ziehl-Neelsen stain was negative. AsciticADA level was high (107,1 U/L).


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Formulate clinical question

In practice, we are facing with diagnostic problem of thispatient with exudative asites and lymphocyte predominantpleiocytosis her ascitic fluid that suggestive a peritonealtuberculosis but ascitic fluid revealed negative for AFB

Gold standard for diagnosis of PTB either time consuming orinvasive, so we tried to find other rapid diagnostic tool

We were informed that ADA level can be used to determinewhether her ascites was due to TB infection or not, but we stilldid not know about the accuracy of this assay

Therefore, we formulate clinical question: What is the value ofascitic fluid ADA for the diagnosis of peritoneal tuberculosis?


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Searching the evidence


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Result

5 articles included:

Riquelme et al, 2006

Saleh et al, 2012

Sharma et al, 2006

Burgess et al, 2001

Sathar et al, 1995

Meta-analysis was appraised using Q-FAST tool

Other 4 prospective studies was appraised for its

VIA


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Critical appraisalItem Summary of Riquelme et al, 2006Q-question The study was based on clear clinical question and it is similar to oursF-finding Inclusion criteria and search methods are stated in the methods section,

inclusion criteria were based on the clinical question.A primary search of the literature was conducted including MEDLINE(PubMed) and hand searching, no limits regarding language4 prospective studies were included in the meta-analysis

A-appraise Individual prospective studies were critically appraised by twoindependent reviewers, agreement between reviewers for article selectionwas measured as kappa coefficient of only 0.43 (moderate), probabledue to small number of selected articles.

S-synthesis The paper includes a clear summary table of the included studies andheterogeneity analysis was done. Four individual studies were homogen.

T-transferability The result of study was applicable on our patient because similarity in thedomain, determinant and outcome.


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Validity

Study Independent andblind comparison Appropriatespectrum of patient Reference standardascertained regardless

of the index test result

Saleh et al, 2012 Yes Yes YesSharma et al, 2006 Yes Yes Yes

Burgess et al, 2001 Yes Yes Yes

Sathar et al, 1995 Yes Yes Yes


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Importance

Study N Best ROC curvecut-off ADAvalue (IU/L)

AUC Sn(%) Sp(%) LRs(+) PPV(%) NPV(%)

Riquelme, et al 264 39 0.99 100 97 26.8 N/A N/ASaleh et al, 2012 41 35 0.99 100 92,6 N/A 87,5 100Sharma et al, 2006 119 37 0.98 97 94 N/A N/A N/A

Burgess et al, 2001 178 30 0.92 94 92 N/A 57 99

Sathar et al, 1995 92 30 0.95 93 96 N/A 93 96


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Applicability

Study The test is available,affordable, accurate

and precise in oursetting

Ability to generate anestimate of patients

pre-test probabilityThe resulting post-testprobabilities will affectmanagement and help

patient

Saleh et al, 2012 Yes Yes YesSharma et al, 2006 Yes Yes Yes

Burgess et al, 2001 Yes Yes Yes

Sathar et al, 1995

Yes

Yes

Yes


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Discussion

All studies agreed that ADA is increased in tuberculousascitic fluid because of the stimulation of T cells by themycobacterial antigens, sensitivity and specificity levelsover 90% have been reported in all studies.

We admit that we might have missed relevant articles, we

excluded all hits that were not in English publication andnot available with full text on the Internet, which can be anegative contributor.

When applying the results of best available evidence toour patient, we have to consider that the meta-analysisincluded population from Chile and India, where a higherfrequency of TB was observed and was similar to ours,where TB is endemic.

Therefore, we can extrapolate the result on our patient.


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Discussion

Our patient with clinicalfeatures suggestive of PTB,has a 50% pretest probabilityof having PTB.

If the ascites fluid study shows

an ADA level of 107 IU/L (>39,LR+ 26.8) she therefore has a96 % posttest probability ofhaving PTB.

The clinical relevance of thistest is evident ever because it

may avoid the need toconfirm the diagnosis withinvasive techniques such aslaparoscopy.


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Discussion

Then, we decide to treat our patient with a 4-drugcombination of anti-tuberculosis.

However, the CDC in United State insists the need

of a sensitivity in vitro test in every patient with PTBto determine the epidemiology of MTB.

It is known that even using the most advancedtechniques to isolate the Mycobacterium, the rate

of positive test is still low and we consider ADAactivity is a practical and useful approach to maketherapeutic decision in patients suspected PTB.


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Discussion

After 8 weeks of anti-tuberculosis treatment, onthe follow up of our patient, she recovered fromconstitutional symptoms and her abdominalcircumference was reduced from 112 cm to 102

cm.

She was planned to have a 9-month course ofanti-tuberculosis drugs that consist of 2 months ofinitial phase and 7 months of continuation phase.


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Conclusion

Measurement of an ascitic ADA activity yields a high

rate of diagnostic accuracy for PTB and it is an easy

available test.

It may help clinicians to decide whether or not to treat

patients with ascites who clinically suspicious for PTB.

To start empirical treatment on a patient with high ADA

value in ascitic fluid seems to be a good approach

while waiting for the results of cultures or biopsies.

We do recommend the utilization of this test in the

diagnostic work-up of patients with suspected PTB.


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Thank you

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