system.

6,7 Despite the presence of multiple studies

that repeatedly have proven this assumption to be
false and a world literature replete with reports of
the success of directly observed therapy, these centers contend that there is no firm evidence demonstrating that directly observed therapy is both effective and essential in the treatment of tuberculosis.
It is time for physician organizations from all parts
of the international community to reject such folly
and firmly endorse directly observed therapy as the
professional standard of care. And as a corollary
standard, as soon as a patient is identified as not
adhering to treatment appointments and cannot be
induced to cooperate with directly observed therapy
(even when provided with a range of social supports),
public health officials should immediately direct that
patient into a specialized tuberculosis treatment
center. If we fully and appropriately treat all patients
during their first encounter with tuberculosis, including the use of specialized facilities where necessary, the risk and the fear of MDR tuberculosis can
fade into history.
The alternative is to stand by and watch as the
tidepools described by Iseman slowly enlarge and
perhaps return as a flood tide.
John A. Sbarbaro, MD, MPH, FCCP
Denver, CO
Dr. Sbarbaro is Professor of Medicine and Preventive Medicine,
University of Colorado Health Sciences Center, Denver, CO.
Correspondence to: John A. Sbarbaro, MD, MPH, FCCP, Professor of Medicine and Preventive Medicine, 4200 E Ninth Ave,
Denver, CO 80262

References
1 Iseman M. ASTER Challenge Lecture. Paper presented at:
IUATLD meeting; November 1992; Paris, France
2 Reported tuberculosis in the United States 1996, 1997, 1998,
1999 reports. US Department of Health and Human Services,
Public Health Service, Centers for Disease Control and Prevention, National Center for HIV, STD, and TB Prevention,
Division of Tuberculosis Elimination. Atlanta, GA: Centers for
Disease Control and Prevention, 1999
3. Snider DE, Kelly GD, Cauthen GM, et al. Infection and
disease among contacts of tuberculosis cases with drugresistant and drug susceptible bacilli. Am Rev Respir Dis
1985; 132:125132
4. Behr MA, Warren SA, Salamon H, et al. Transmission of
Mycobacterium tuberculosis from patients smear-negative for
acid-fast bacilli. Lancet 1999; 353:444 449
5. Braden CR. Infectiousness of a university student with laryngeal and cavitary tuberculosis. Clin Infect Dis 1995; 21:565
570
6. Ogden J. The resurgence of tuberculosis in the tropics:
improving tuberculosis control; social science inputs. Trans R
Soc Trop Med 2000; 94:135140
7. Porter J, Ogden J, Pronyk P. The way forward: an integrated
approach to tuberculosis. In: Porter J, Grange J, eds. Tuberculosis: an interdisciplinary perspective. London, UK: Imperial College Press, 1999
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Smear-Negative Pulmonary
Tuberculosis in Industrialized
Countries
attention has recently been paid to the
M uch
problem of smear-negative pulmonary tuberculosis. Quite appropriately, the discussion has focused
on low-income countries, home to the vast majority
of individuals with tuberculosis and HIV and where
the ability to culture diagnostic specimens may be
lacking.15 Yet, there remain legitimate questions
concerning this group of patients in industrialized
countries. In this issue of CHEST (see page 349),
Kanaya et al address one of those questions. Is it
possible to predict, among patients with suspected
active, smear-negative pulmonary tuberculosis, those
patients whose culture specimens will ultimately
prove to be positive? The object would be to avoid
the adverse consequences that might result from
withholding treatment in patients with the disease
(remaining ill for excessively long periods of time,
and possibly infecting others in the community) or
introducing treatment in patients without the disease
(their actual illness goes untreated, and they are
exposed unnecessarily to possible drug toxicity).
The problem of smear-negative pulmonary tuberculosis is not trivial. In acute-care settings, as many
as 8 to 10 patients are suspected to have tuberculosis
for every one confirmed case.6,7 In our provincial
jurisdiction, respiratory specimens from 125 persons
are submitted, on average, for every one cultureconfirmed case of tuberculosis.
Presently the most important criteria for establishing a presumptive diagnosis of tuberculosis are the
acid-fast bacilli (AFB) smear (performed on clinical
specimens that are adequate in both quantity and
quality) and a case definition, which may be based on
radiographic signs, clinical findings, risk factors, or a
combination of these factors.8 The sensitivity of the
AFB smear result is known to be poor, varying
between 30% and 70% depending on a number of
factors relating to how the test is implemented.3 The
sensitivity is improved by concentration of sputum
specimens and use of fluorescent microscopy but
reduced in patients with HIV disease.3,5 The specificity and positive predictive value of the smear
results may be reduced in settings of high HIV
prevalence or low (high nontuberculous mycobacterial [NTM]) tuberculosis prevalence.9 Yet, the sputum smear should always be performed because it is
quick and easy to activate, provides preliminary
confirmation of the diagnosis, and gives a quantitative estimate of the number of bacilli being excreted
and therefore the infectivity of the patient ( 5,000
bacilli per milliliter of sputum must usually be
Editorials

present for the smear result to be positive).9 In the

initial evaluation, a nucleic acid amplification (NAA)
test may allow for a distinction between a positive
smear result due to Mycobacterium tuberculosis and
one due to an NTM (see below).9 But if this test is
not available, then the positive smear result should
be interpreted to mean the presence of infectious
tuberculosis until proven otherwise. False-negative
smear results may occur (Table 1), and efforts to
limit this error must be ongoing.10
Truly negative smear results, of course, do not
preclude tuberculosis disease. Culture of clinical
specimens will confirm the diagnosis in smear-positive cases and usually identify that many cases again
of smear-negative disease. This is because the culture is more sensitive (80 to 85%), being able to
detect as few as 10 bacteria per milliliter of sputum.9,11 It is also very specific (98%)12,13 and allows
drug susceptibility testing as well as genotyping of
the isolate. Unfortunately, the time to detection and
speciation of cultures, even with selective liquid
media and nucleic acid probes, may be up to 7
weeks, particularly when the burden and metabolic
activity of the mycobacteria are very low, as is often
the case in smear-negative, culture-positive disease.
It is this time window, the sensitivity gap between
the smear and the culture, that prediction rules such
as those proposed by Kanaya et al aim to close. They
do not address the suspect case that is ultimately
bacillary (smear and culture) negative. In our jurisdiction, 75% of all notified tuberculosis cases are
respiratory; of these, 38% are smear-positive and
culture positive, 48% are smear-negative and culture-positive, and 14% are smear-negative and culture-negative.14 Culture positivity antedated the start
date of treatment in 54% of smear-negative, culturepositive respiratory cases. For every smear-positive
respiratory case, there were 2.52 smear-negative
respiratory or nonrespiratory cases.

Table 1Causes of a False-Negative Sputum

Smear Finding*
Stages

Cause

Sputum collection

Inadequate sputum sample

Inappropriate sputum container
Sputum stored too long before microscopic
examination
Faulty sampling for smear
Faulty smear preparation and staining
Inadequate time spent examining smear
Inadequate attention to smear
Misidentification of patient
Incorrect labeling of sample
Mistakes in documentation

Sputum processing
Smear examination
Administration

*Adapted from Toman.10

A replacement for culture that is equally sensitive

and specific, but more rapid, is clearly needed if
patients with early-stage disease, low burden infection, and minimal symptoms are to be detected.15
Technologies that allow for the amplification of
specific target sequences of nucleic acids that can
then be detected through the use of a nucleic acid
probe currently offer the greatest promise of direct
detection and identification of M tuberculosis in
clinical specimens. To paraphrase the recent American Thoracic Society (ATS) statement on Diagnostic
Standards and Classification of Tuberculosis in
Adults and Children9: NAA methods can be applied
to clinical specimens within hours. In respiratory
specimens that are AFB smear positive, their sensitivity is approximately 95% with a specificity of 98%.
In specimens that contain fewer organisms and are
AFB smear-negative, results are positive in 48 to
53% of patients with culture-positive tuberculosis
and the specificity remains approximately 95%.16 An
enhanced NAA test has been approved by the
Food and Drug Administration advisory panel for
use on both smear-positive and smear-negative respiratory specimens from patients who are clinically
suspected of having tuberculosis. This recommendation is based on a clinical trial in which the suspicion of tuberculosis was quantified.17 In patients
(AFB smear-positive and smear-negative) where the
clinician had an intermediate or high suspicion of
tuberculosis disease, the sensitivity of the enhanced
test was 75 to 88% and the specificity was 100%. The
clinical use of NAA tests in this setting has to be
confirmed, and efforts to clarify appropriate uses are
underway.16,18
Earlier definitive diagnosis of the smear-negative
case will impact clinical (treatment) and public
health (isolation and contact investigation) decision
making. Currently, these decisions must be made in
the absence of a definitive diagnosis. They require a
sophisticated analysis of all available information and
an estimate of relative risk. Prediction rules may help
in this regard, but they must be understood to reflect
the population under study, both patients and physicians. Factors likely to affect physicians estimates
of relative risk include the customary prevalence of
disease in the practice setting, the clinical spectrum
of disease, the specialty or experience of the physician, and the quality of the medical history.19 Prediction rules are also subject to bias, as a more
determined effort to seek the diagnosis, and therefore recover the organism, usually attends a higher
level of suspicion. At its workshop on rapid diagnostic tests,16 the ATS developed an algorithm in which
the decision to treat, isolate, or commence contact
investigation was based on an integration of the
following variables: high or low clinical suspicion of
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331

tuberculosis, AFB smear-positive or smear-negative

results, and positive or negative NAA test results.
Actions were compared with or without knowledge
of the NAA test. The algorithm was not intended to
represent an official recommendation from either
the Centers for Disease Control and Prevention or
the ATS. In a cogent companion editorial, Peter
Barnes20 presented guidelines to assist clinicians in
using NAA tests and interpreting their results. To the
extent that NAA test results lead to deferral of
further diagnostic evaluation, they may reduce the
yield in culture and the benefits that accrue from
recovery of the organism. Ultimately, phage replication systems that can be used for both detection and
drug susceptibility testing of live mycobacteria may
have greater utility.2123
A decision to treat a patient with smear-negative
finding may influence diagnosis (evidence for or
against a therapeutic response) and infectivity (a
patient with a smear-negative and ultimately culturepositive finding may be considered noninfectious
after 2 weeks of effective treatment24). A decision to
treat may or may not intimate a public health action
and vice versa.7,2528
In deciding whether or not to introduce treatment,
we have found it helpful to classify patients with
smear-negative, culture-positive findings into one of
three groups: (1) patients with primary pulmonary
tuberculosis who are not HIV coinfected (group 1);
(2) patients with primary or postprimary pulmonary
tuberculosis who are HIV coinfected (group 2); and
(3) patients with postprimary tuberculosis who are
not HIV coinfected (group 3).
Group 1 patients usually have noncavitary, relatively paucibacillary tuberculosis. Not uncommonly,
their specimens are culture-negative.9 Their diagnosis is dependent on a good history of tuberculosis
contact, a positive tuberculin skin test (TST) result or
possibly a TST conversion, and a compatible clinical
and radiographic picture. Group 1 patients are often
children, and they should be treated promptly, as
there is a risk of progression to more sinister forms of
disease (neurotuberculosis or disseminated disease).
Likewise, treatment with antituberculosis drugs
should be initiated promptly in group 2 patients, as
both tuberculosis disease and HIV replication may
accelerate in their absence.29,30 Unfortunately, making a presumptive diagnosis of tuberculosis in patients with advanced HIV disease is not a simple task.
Their chest radiographs may be atypical, their histopathologic findings misleading, and their TST results falsely negative. The differential diagnosis may
be broad.29 The overall characteristics of NAA tests
may be uniquely well suited to this population.17,30
From a bacteriologic point of view, patients in
group 3 appear to be different from HIV-uninfected
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Table 2Factors Influencing the Decision to Place a

Sputum Smear-Negative, HIV-Seronegative Patient
With Suspect Active (ie, as yet Unconfirmed by
Culture) Postprimary Pulmonary Tuberculosis on
Antituberculosis Drugs
History of tuberculosis contact
History of tuberculosis and the adequacy/inadequacy of its
treatment
Presence of a medical condition that may increase the likelihood of
progression from infection to disease
Presence of compatible symptoms35
Presence of a progressive abnormality on serial chest radiographs,
particularly if the abnormality involves one or both upper lung
zones
Presence of a CT thorax demonstrating endobronchial disease36
Presence of a transbronchial or surgical biopsy or fine-needle
aspirate demonstrating granulomata, particularly if the
granulomata are caseating and associated with a positive smear
finding on special stain
Presence of a positive TST result
Absence of another explanation for the illness
Likelihood of toxicity from the antituberculosis drugs
Transmission risk
Reliability of follow-up

patients with smear-positive, culture-positive

postprimary pulmonary tuberculosis.10,3133 First,
they have been demonstrated to be discharging small
numbers of bacilli intermittently.10 Secondly, their
infectivity is very much lower than that of patients
with smear-positive findings.34 Third, the minimal
extent of their disease does not, as one might expect,
automatically imply that they are in an early stage of
what will become smear-positive cavitary disease.10,31 And fourth, their prognosis is often very
good even without treatment.10 Thus, their natural
history is usually more benign than that of patients
with smear-positive sputum findings. That much is
lost by not initiating treatment in some of these
patients at the point of suspicion is not at all a given.
On the contrary, it may be more appropriate to
investigate these patients until a diagnosis is established rather than treating empirically. Certainly if a
life-threatening form of nonrespiratory tuberculosis
is suspected of being coexistent, then treatment must
be instituted promptly. Among group 3 smear-negative, culture-positive patients, it is not established
that transmission is greater from those who begin
treatment at the point when culture results are found
to be positive than those who begin treatment at the
point of suspicion. Prudence would dictate that each
of these cases be considered individually, with the
relative importance of a broad range of determinants, only some of which may be at hand, weighted
(Table 2).
Because prediction rules combine in a single score
items that would have vastly different levels of
Editorials

importance in different clinical contexts, we remain

skeptical that they add much to the decision-making
process. Their validation in prospective studies is
important.
ACKNOWLEDGMENT: The author is very grateful to Lisa
Meyers, MLT, and Michele Zielinski, BScN, for technical assistance; Drs. Alex Herbert, Earl Hershfield, Dennis Kunimoto,
Vernon Hoeppner, and Bruce Light for their review of the
article, and Cassandra Martin and Joanne Leroux for preparation
of the article.

Richard Long, MD, FCCP

Edmonton, Alberta, Canada
Dr. Long is a professor in the Pulmonary Division, Department
of Medicine, University of Alberta.
Correspondence to: Richard Long, MD, FCCP, Department of
Medicine, University of Alberta, Room 2E4.21, Walter C. Mackenzie Center, 8440 112 St, Edmonton, Alberta T6G 2B7, Canada; e-mail: richard.long@ualberta.ca

References
1 Nunn PP, Elliott AM, McAdam KPWJ. Impact of human
immunodeficiency virus on tuberculosis in developing countries. Thorax 1994; 49:511518
2 Ipuge YAI, Rieder HL, Enarson DA. The yield of acid-fast
bacilli from serial smears in routine microscopy laboratories.
Trans R Soc Trop Med Hyg 1996; 90:258 261
3 Foulds J, OBrien R. New tools for the diagnosis of tuberculosis: the perspective of developing countries. Int J Tuberc
Lung Dis 1998; 2:778 783
4 Harries AD, Maher D, Nunn P. An approach to the problems
of diagnosing and treating adult smear-negative pulmonary
tuberculosis in high-HIV-prevalence settings in sub-Saharan
Africa. Bull World Health Org 1998; 76:651 662
5 Colebunders R, Bastian I. A review of the diagnosis and
treatment of smear-negative pulmonary tuberculosis. Int J
Tuberc Lung Dis 2000; 4:97107
6 Blumberg HM, Watkins DL, Berschling JD, et al. Preventing
the nosocomial transmission of tuberculosis. Ann Intern Med
1995; 122:658 653
7 Bock NN, McGowan JE Jr, Ahn J, et al. Clinical predictors of
tuberculosis as a guide for a respiratory isolation policy. Am J
Respir Crit Care Med 1996; 154:1468 1472
8 Gordin FM, Slutkin G, Schecter G, et al. Presumptive diagnosis
and treatment of pulmonary tuberculosis based on radiographic
findings. Am Rev Respir Dis 1989; 139:1090 1093
9 Dunlap NE, Bass J, Fujiwara P, et al. Diagnostic standards
and classification of tuberculosis in adults and children. Am J
Respir Crit Care Med 2000; 161:1376 1395
10 Toman K. Tuberculosis case-finding and chemotherapy:
questions and answers. Geneva, Switzerland: World Health
Organization, 1979
11 Yeager HJ Jr, Lacy J, Smith L, et al. Quantitative studies of
mycobacterial populations in sputum and saliva. Am Rev
Respir Dis 1967; 95:998 1004
12 Morgan MA, Horstmeier CD, De Young DR, et al. Comparison of a radiometric method (Bactec) and conventional
culture media for recovery of mycobacteria from smearnegative specimens. J Clin Microbiol 1983; 18:384 388
13 Ichiyama S, Shimokata K, Takeuchi J, et al. Comparative
study of a biphasic culture system (Roche MB Check System)
with a conventional egg medium for recovery of mycobacteria. Tuberc Lung Dis 1993; 74:338 341

14 Long R, Chui L, Kakulphimp J, et al. Postsanitorium pattern

of antituberculous drug resistance in Western Canada: effect
of outpatient care and immigration. Am J Epidemiol 2001;
153:903911
15 Perkins MD. New diagnostic tools for tuberculosis. Int J
Tuberc Lung Dis 2000; 4:S182S188
16 American Thoracic Society. Rapid diagnostic tests for tuberculosis: what is the appropriate use? Am J Respir Crit Care
Med 1997; 155:1804 1814
17 Perry S, Catanzaro A. Use of clinical risk assessments in
evaluation of nucleic acid amplification tests for HIV/tuberculosis. Int J Tuberc Lung Dis 2000; 4:534 540
18 Catanzaro A, Perry S, Clarridge JE, et al. The role of clinical
suspicion in evaluating a new diagnostic test for active
tuberculosis: results of a multi-center prospective trial. JAMA
2000; 283:639 645
19 Schulman KA, Escarce JJ, Eisenberg JM, et al. Assessing
physicians estimation of the probability of coronary artery
disease. Med Decis Making 1992; 12:109 114
20 Barnes PF. Rapid diagnostic tests for tuberculosis: progress
but no gold standard. Am J Respir Crit Care Med 1997;
155:14971498
21 McNerney R, Wilson SM, Sidhu AM, et al. Inactivation of
mycobacterophage S29 using ferrous ammonium sulfate as a
tool for the detection of viable Mycobacterium smegmatis and
M. tuberculosis. Res Microbiol 1998; 149:487 495
22 Wilson SM, al Suwaidi Z, McNerney R, et al. Evaluation of a
new rapid bacteriophage-based method for drug susceptibility testing of Mycobacterium tuberculosis. Nat Med 1997;
3:465 468
23 Eltringham IJ, Drobniewski FA, Mangan JA, et al. Evaluation
of a reverse transcription-PCR and a bacteriophage-based
assay for rapid phenotypic detection of rifampin resistance in
clinical isolates of Mycobacterium tuberculosis. J Clin Microbiol 1999; 37:3524 3527
24 Menzies D. Effect of treatment on contagiousness of patients
with active pulmonary tuberculosis. Infect Control Hosp
Epidemiol 1997; 18:582586
25 Scott B, Schmid M, Nettleman MD. Early identification and
isolation of inpatients at high risk for tuberculosis. Arch
Intern Med 1994; 154:326 330
26 El-Solh A, Mylotte J, Sherif S, et al. Validity of a decision tree
for predicting active pulmonary tuberculosis. Am J Respir
Crit Care Med 1997; 155:17111716
27 Redd JT, Susser E. Controlling tuberculosis in an urban
emergency department: a rapid decision instrument for patient isolation. Am J Public Health 1997; 87:15431547
28 Sokolove PE, Lee BS, Krawczyk JA, et al. Implementation of
an emergency department triage procedure for the detection
and isolation of patients with active pulmonary tuberculosis.
Ann Emerg Med 2000; 35:327336
29 Hopewell PC, Chiasson RE. Tuberculosis and human immunodeficiency virus infection. In: Reichman LB, Hershfield
ES, eds. Tuberculosis a comprehensive international approach. New York, NY: Marcel Dekker, 2000; 525552
30 Havlir DV, Barnes PF. Tuberculosis in patients with human
immunodeficiency virus infection. N Engl J Med 1999;
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31 Hong Kong Chest Service/Tuberculosis Research Center,
Madras/British Medical Research Council. A study of the
characteristics and course of sputum smear-negative pulmonary tuberculosis. Tubercle 1981; 62:155167
32 Kim TC, Blackman RS, Heatwole KM, et al. Acid-fast bacilli
in sputum smears of patients with pulmonary tuberculosis.
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33 Dutt AK, Stead WW. Smear-negative pulmonary tuberculosis. Semin Respir Infect 1994; 9:113119
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34 Grzybowski S, Barnett GD, Styblo K. Contacts of cases of

active pulmonary tuberculosis. Bull Int Union Tuberc 1975;
50:90 106
35 Miller LG, Asch S, Yu EI, et al. A population-based survey of
tuberculosis symptoms: how atypical are atypical presentations. Clin Infect Dis 2000; 30:293299
36 Long R, Maycher B, Dhar A, et al. Pulmonary tuberculosis
treated with directly observed therapy: serial changes in lung
structure and function. Chest 1998; 113:933943

Adenosine Deaminase in the

Diagnosis of Tuberculous
Pleural Effusion
n some parts of the United States, pleural tuberI culosis
accounts for 5% of all cases of tuberculosis.1 In some countries, the incidence of pleural
tuberculosis is much higher. It is generally linked to
the local prevalence of tuberculosis. Pleurisy with
effusion as a complication of primary pulmonary
tuberculosis has been reported to occur in 2 to 38%
of children with pulmonary disease, but it is more
likely to occur in adolescents and adults.2 8 However, tuberculous pleural effusion in older patients
with classic reactivation of tuberculosis also can
occur.1 Tuberculous pleural effusion is thought to
result from a delayed hypersensitivity reaction in
response to the presence of mycobacterial antigens in the pleural space.9 These mycobacterial
antigens may gain access to the pleural space from
the rupture of a small subpleural focus.10 A significant number of patients (50 to 59%) with primary
tuberculosis who develop pleural effusion may
have roentgenographically apparent parenchymal
tuberculosis.1,8 Delayed hypersensitivity reaction
causes the stimulation and differentiation of lymphocytes that perform a variety of functions, including the release of certain lymphokines that
activate macrophages for enhanced mycobactericidal effect.11
The diagnosis of tuberculous pleural effusion can
be difficult because of the low sensitivity of the
various diagnostic tools. Lymphocytic exudate seen
in tuberculous pleural effusion also can occur in
other diseases such as malignancy and collagen
vascular diseases (ie, rheumatoid arthritis and systemic lupus erythematosus).1214 Cultures for acidfast bacilli are positive in 20 to 30% of pleural fluid
samples and in 50 to 80% of pleural biopsy specimens.15,16 The sensitivity of polymerase chain reaction for active disease is 78%.17 The cutaneous
response to purified protein derivative may also be
negative in one third of the patients.18 Thus, despite
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a comprehensive evaluation, almost 20% of tuberculous pleural fluids will defy a definitive diagnosis.
The reliability of the early diagnosis of pleural
tuberculosis has been greatly improved by the use of
biochemical markers such as adenosine deaminase
(ADA), interferon-, and lysozyme.12,18 21 The determination of the ADA level in the suspected
pleural fluid appears to be the most promising
marker because of the ease, rapidity, and costeffectiveness of the ADA assay. ADA is found in
most cells, but its chief role concerns the proliferation and differentiation of lymphocytes, especially
T-lymphocytes. For that reason ADA has been
looked on as a marker of cell-mediated immunity,
which encompasses the delayed hypersensitivity reaction.
The determination of ADA activity was first proposed as a serologic diagnostic marker for lung
cancer in 1970.22 Later, Piras et al23 in 1978 reported
the usefulness of ADA in diagnosing tuberculous
pleurisy. ADA is an enzyme involved in the purine
catabolism. It catalyzes the deamination of adenosine
to inosine and of deoxyadenosine to deoxyinosine.
There are several isoforms of ADA, but the prominent ones are ADA1 and ADA2, which are coded by
different gene loci.24 ADA1 isoenzyme is found in all
cells, with the highest concentration found in lymphocytes and monocytes, whereas ADA2 isoenzyme
appears to be found only in monocytes.25 ADA2 is
the predominant isoform in the tuberculous pleural
effusion, accounting for 88% (median) of total ADA
activity, whereas ADA1 is elevated in empyema,
accounting for 70% (median) of total ADA activity.20
This would suggest that ADA2 is the more efficient
marker of tuberculous pleural effusion. However, in
clinical practice, the difference in the use of total
ADA and isoform ADA2 is not significant. In fact,
there is an advantage in the measurement of total
ADA because of its low cost and rapid turnover.
ADA1 activity is determined by subtracting ADA2
from total ADA. The measurement of ADA2 is
almost 10 times more expensive and is not available
in the United States except for research purposes.
The colorimetric method for the measurement of
total ADA described by Guisti and Galanti26 has an
advantage over other methods because of its low
cost, simplicity of technique, and rapid turnover.
With this technique, the sensitivity and specificity of
elevated level of ADA in the tuberculous pleural
fluid ranges from 91 to 100% and 81 to 94%,
respectively.12,19,27,28 The positive and negative predictive values range from 84 to 93% and 89 to 100%,
respectively.12,19,27,28 The reported diagnostic cutoff
value for ADA varies from 40 to 60 U/L,12,18 21,2729
and choosing a lower value will increase sensitivity at
Editorials