STANDARD 4.

All persons with chest radiographic fi ndings suggestive of tuberculosis should
have sputum specimens submitted for microbiological examination.

Rationale and Evidence Summary

Chest radiography is a sensitive but nonspecifi c test to detect tuberculosis.
44 Radiographic examination (fi lm or fl uoroscopy) of the thorax or
other suspected sites of involvement may be useful to identify persons
for further evaluation. However, a diagnosis of tuberculosis cannot be
established by radiography alone. Reliance on the chest radiograph
as the only diagnostic test for tuberculosis will result in both over-diagnosis
of tuberculosis and missed diagnoses of tuberculosis and
other diseases. In a study from India in which 2,229 outpatients
were examined by photofl uorography, 227 were classifi ed as having
tuberculosis by radiographic criteria.45,46 Of the 227, 81 (36%)
had negative sputum cultures, whereas of the remaining 2,002 patients,
31 (1.5%) had positive cultures. Looking at these results in
terms of the sensitivity of chest radiography, 32 (20%) of 162 culturepositive
cases would have been missed by radiography. Given these
and other data, it is clear that the use of radiographic examinations
alone to diagnose tuberculosis is not an acceptable practice.

Chest radiography is useful to evaluate persons who have negative sputum smears to attempt
to find evidence for pulmonary tuberculosis and to identify other abnormalities that
may be responsible for the symptoms. With regard to tuberculosis, radiographic examination
is most useful when applied as part of a systematic approach in the evaluation of
persons whose symptoms and/or fi ndings suggest tuberculosis, but who have negative
sputum smears. (See Standard 5.)

STANDARD 5.

The diagnosis of sputum smear-negative pulmonary tuberculosis should be
based on the following criteria: at least three negative sputum smears (including
at least one early morning specimen); chest radiography fi ndings consistent
with tuberculosis; and lack of response to a trial of broad-spectrum antimicrobial
agents. (NOTE: Because the fl uoroquinolones are active against M. tuberculosis
complex and, thus, may cause transient improvement in persons with
tuberculosis, they should be avoided.) For such patients, if facilities for culture
are available, sputum cultures should be obtained. In persons with known or
suspected HIV infection, the diagnostic evaluation should be expedited.

Rationale and Evidence Summary

The designation of “sputum smear-negative tuberculosis” presents a diffi cult diagnostic
dilemma. As noted above, on average, sputum smear microscopy is only about 50–60%
sensitive when compared with culture. Nevertheless, given the nonspecifi c nature of the
symptoms of tuberculosis and the multiplicity of other diseases that could be the cause
of the patient’s illness, it is important that a rigorous approach be taken in diagnosing
tuberculosis in a patient in whom at least three adequate sputum smears are negative.
Because patients with HIV infection and tuberculosis frequently have negative sputum
smears, and because of the broad differential diagnosis (including Pneumocystis jiroveci
pneumonia and bacterial and fungal lower respiratory infections) in this group, such a systematic
approach is crucial. It is important, however, to balance the need for a systematic
approach, in order to avoid both over- and under-diagnosis of tuberculosis, with the need
for prompt treatment in a patient with an illness that is progressing rapidly. Over-diagnosis
of tuberculosis when the illness has another cause will delay proper diagnosis and treatment;
whereas, under-diagnosis will lead to more severe consequences of tuberculosis,
including disability and possibly death, as well as ongoing transmission of M. tuberculosis.
It should be noted that in making a diagnosis based on the above three criteria, a
clinician who decides to treat with a full course of antituberculosis chemotherapy should
report this as a case of sputum smear-negative pulmonary tuberculosis to local public
health authorities (as described in Standard 17).

A number of algorithms have been developed as a means to systematize the diagnosis
of smear-negative tuberculosis, although none has been adequately validated under fi eld
conditions.47,48 In particular, there is little information or experience on which to base approaches
to the diagnosis of smear-negative tuberculosis in persons with HIV infection.
Figure 1 is modifi ed from an algorithm developed by WHO and is included as an example
of a systematic approach.24 It should be recognized that, commonly, the steps in the algorithm
are not followed in a sequential fashion by a single provider. The algorithm should be
viewed as presenting an approach to diagnosis that incorporates the main components
of, and a framework for, the diagnostic evaluation.

There are several points of caution regarding the algorithm. First, completion of all of the
steps requires a substantial amount of time; thus, it should not be used for patients with
an illness that is worsening rapidly. This is especially true in patients with HIV infection
in whom tuberculosis may be rapidly progressive. Second, several studies have shown
that patients with tuberculosis may respond, at least transiently, to broad spectrum antimicrobial treatment.49–52 Obviously, such a response will lead one to delay a diagnosis
of tuberculosis. Fluoroquinolones in particular are bactericidal for M. tuberculosis
complex. Empiric fl uoroquinolone monotherapy for respiratory tract infections has been
associated with delays in initiation of appropriate antituberculosis therapy and acquired
resistance to the fl uoroquinolones.53 Third, the approach outlined in the algorithm may
be quite costly to the patient and deter her/him from continuing with the diagnostic
evaluation. Given all these concerns, application of such an algorithm in patients with at
least three negative sputum smear examinations must be done in a fl exible manner. Ideally,
the evaluation of smear-negative tuberculosis should be guided by locally validated
approaches, suited to local conditions.

FIGURE 1.

An illustrative approach to the diagnosis of sputum smear-negative
pulmonary tuberculosis²⁴

Although sputum microscopy is the first bacteriologic diagnostic test of choice
where resources permit and adequate, quality-assured laboratory facilities
are available, culture should be included in the algorithm for evaluating patients
with negative sputum smears. Properly done, culture adds a signifi
cant layer of complexity and cost but also increases sensitivity, which
should result in earlier case detection.54,55 Although the results of culture
may not be available until after a decision to begin treatment has to be
made, treatment can be stopped subsequently if cultures from a reliable
laboratory are negative, the patient has not responded clinically,
and the clinician has sought other evidence in pursuing the differential
diagnosis.

The probability of finding acid-fast bacilli in sputum smears by microscopy
is directly related to the concentration of bacilli in the sputum. Sputum
microscopy is likely to be positive when there are at least 10,000
organisms per milliliter of sputum. At concentrations below 1,000 organisms
per milliliter of sputum, the chance of observing acid-fast bacilli in a smear is less than
10%.56,57 In contrast, a properly performed culture can detect far lower numbers of acidfast
bacilli (detection limit is about 100 organisms per ml).54 The culture, therefore, has
a higher sensitivity than microscopy and, at least in theory, can increase case detection,
although this potential has not been demonstrated in low-income, high-incidence areas.
Further, culture makes it possible to identify the mycobacterial species and to perform
drug susceptibility testing in patients in whom there is reason to suspect drug-resistant
tuberculosis.54 The disadvantages of culture are its cost, technical complexity, and the
time required to obtain a result, thereby imposing a diagnostic delay if there is less reliance
on sputum smear microscopy. In addition, ongoing quality assessment is essential for
culture results to be credible. Such quality assurance measures are not available widely in
most low-resource settings.

In many countries, although culture facilities are not uniformly available, there is the capacity
to perform culture in some areas. Providers should be aware of the local capacity
and use the resources appropriately, especially for the evaluation of persons suspected
of having tuberculosis who have negative sputum smears and for persons suspected of
having tuberculosis caused by drug-resistant organisms.
Traditional culture methods use solid media such as Lowenstein-Jensen and Ogawa.
Cultures on solid media are less technology-intensive, and the media can be made locally.

However, the time to identify growth is significantly longer than in liquid media. Liquid
media systems such as BACTEC® utilize the release of radioactive CO2 from C-14 labeled
palmitic acid in the media to identify growth. The MGIT® system, also using liquid medium,
has the advantage of having growth detected by the appearance of fl uorescence in
a silicone plug at the bottom of the tube, thereby avoiding radioactivity. Decisions to provide
culture facilities for diagnosing tuberculosis depend on fi nancial resources, trained
personnel, and the ready availability of reagents and equipment service.
Nucleic acid amplifi cation tests (NAATs), although widely distributed, do not offer major
advantages over culture at this time. Although a positive result can be obtained more
quickly than with any of the culture methods, the NAATs are not suffi ciently sensitive for a
negative result to exclude tuberculosis.58–63 In addition, NAATs are not suffi ciently sensitive
to be useful in identifying M. tuberculosis in specimens from extrapulmonary sites of disease.
59–61,63 Moreover, cultures must be available if drug susceptibility testing is to be performed.
Other approaches to establishing a diagnosis of tuberculosis, such as serological
tests, are not of proven value and should not be used in routine practice at this time.58