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of the proximal airway pressure, and “transmission” of alveolar pressure to the local environment that surrounds the bronchial channel is likely to be greater. In these open zones, however, the delicate alveolar septae may overdistend. Precisely
this distribution of histologic lesions was demonstrated in the
study by Goldstein and colleagues (3).
In the clinical setting, higher pressures applied over extended periods can cause radiographic evidence of airspace
coalescence as the inflamed lung remodels under the influence
of heightened tissue stress. Cystic spaces may form throughout
the lungs of patients with ARDS, with a greater prevalence in
dependent regions (8). Tension gas cysts, which are a pathologically distinct subgroup (9), arise from extraalveolar gas
that fails to decompress into the mediastinum. These tend to
develop suddenly in juxtapleural regions, and presage lifethreatening lung rupture or systemic gas embolism (9, 10).
Long-term structural changes in ARDS are a joint function
of the nature and intensity of the inflammation, the substrate
of the lung, and the remodeling forces of ventilating pressure.
Although lung fibrosis is generally acknowledged to be the
most frequent complication of ARDS, disability resulting from
residual airway damage is not uncommon. Six months and
longer after discharge from the hospital, ⵑ 20% of patients
have functional abnormalities of airflow, and ⵑ 40% show
impaired diffusing capacity that might, in part, reflect the
lasting consequences of bronchial damage and airspace dilation (11, 12).
In reemphasizing that airspace damage may occur unnoticed at modest airway pressures, the current report defines a
focus for further study and suggests an important clinical message. Moreover, it calls attention to the insights that may be
gained from long-duration studies of ventilation. Considerably
more must be learned regarding possible modifiers such as infection, vascular pressure, position, inspired oxygen concentration, and antiinflammatory agents. Understanding such interactions may help us to assign a portion of the blame for death
and lingering disability from ARDS to correctable iatrogenic
contributors, and thereby improve outcome.
JOHN J. MARINI
University of Minnesota
St. Paul, Minnesota
References
1. Tomashefski JF. Pulmonary pathology of the adult respiratory distress
syndrome. Clin Chest Med 1990;11:593–619.
2. Smyth LJ, Tabachnick E, Duncan WJ, Reilly BJ, Levison H. Pulmonary
function and bronchial reactivity in long-term survivors of bronchopulmonary dysplasia. Pediatrics 1981;68:336–340.
3. Goldstein I, Bughalo M-T, Marquette C-H, Lanaour G, Lu, Q, Rouby J-J,
Experimental ICU Study Group. Mechanical ventilation-induced airspace enlargement during experimental pneumonia in piglets. Am J
Respir Crit Care Med 2001;163:958–964.
4. Mead J, Takashima T, Leith D. Stress distribution in lungs: a model of
pulmonary elasticity. J Appl Physiol 1970;28:596–608.
5. Maunder RJ, Shuman WP, McHugh JW, Marglin SI, Butler J. Preservation of normal lung regions in the adult respiratory distress syndrome:
analysis by computed tomography. JAMA 1986;255:2463–2465.
6. Broccard AF, Shapiro RS, Scmitz LL, Ravenscraft SA, Marini JJ. Influence of prone position on extent and distribution of lung injury in a
high tidal volume oleic acid injury model of acute respiratory distress
syndrome. Crit Care Med 1997;25:16–27.
7. Van der Kloot TE, Blanch L, Youngblood AM, Weinert C, Adams AB,
Marini JJ, Shapiro RS, Nahum A. Recruitment maneuvers in three experimental models of acute lung injury. Am J Respir Crit Care Med
2000;161:1485–1494.
8. Gattinoni L, Bombino M, Pelosi P, Lissoni A, Pesenti A, Fumagalli R,
Tagliabue M. Lung structure and function in different stages of the
adult respiratory distress syndrome. JAMA 1994;271:1772–1779.
9. Albelda SM, Gefter WB, Kelley MA. Ventilator induced subpleural air
cysts: clinical, radiographic and pathologic significance. Am Rev Respir
Dis 1983;127:360–365.
10. Marini JJ, Culver BH. Systemic gas embolism complicating mechanical
ventilation in the adult respiratory distress syndrome. Ann Intern Med
1989;110:699–703.
11. Finfer S, Rocker G. Alveolar overdistension is an important mechanism
of persistent lung damage following severe, protracted ARDS. Anaesth
Int Care 1996;24:569–573.
12. Ingbar DDH, Wendt CH. Outcome in survivors of the adult respiratory
distress syndrome. Semin Respir Crit Care Med 1994;15:335–348.
Diagnosing Latent Tuberculosis Infection
The 100-year Upgrade
In many industrialized nations, tuberculosis case rates have
declined significantly during the past decade, and elimination
of tuberculosis is a realistic goal that hinges on treating latent
tuberculosis infection (LTBI) to prevent development of disease. Whereas a vast array of molecular and immunologic
tools is available to diagnose many infectious diseases, detection of LTBI is still based on the tuberculin skin test, a century-old test that measures the size of a bump under the skin
that develops in response to a crude mixture of mycobacterial
antigens. Because some antigens are shared with other mycobacteria, tuberculin reactivity can result from immunization
with BCG or from exposure to environmental mycobacteria.
In addition, two visits are required for administration and interpretation of the test.
The QuantiFERON-TB test (CSL Biosciences, Melbourne,
Australia) is the only commercially available blood test to detect LTBI on the basis of production of higher concentrations
of interferon ␥ (IFN-␥) by cells in response to Mycobacterium
tuberculosis than to the predominant environmental mycobac-
terium Mycobacterium avium complex. QuantiFERON-TB test
results correlate well with tuberculin skin test reactivity (1).
However, because multiple M. tuberculosis antigens are used,
some of which are shared with BCG, false-positive results will
probably be obtained in BCG-vaccinated persons.
During the past decade, a major scientific advance has
been the identification of antigens that are expressed by M. tuberculosis, but not by BCG or by most environmental mycobacteria. The best studied of these antigens is the early secreted antigenic target 6-kD protein (ESAT-6) (2–4), which
has multiple epitopes that are recognized by persons of many
different HLA types (5). In persons with LTBI, memory T
cells produce IFN-␥ in response to stimulation in vitro with M.
tuberculosis antigens, and these IFN-␥-producing cells can be
detected by the extremely sensitive enzyme-linked immunospot (ELISPOT) method (6).
In this issue of the American Journal of Respiratory and
Critical Care Medicine, (pp. 824–828) Lalvani and colleagues
utilized these scientific advances to develop what is likely to
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
be the first of a new generation of tests for LTBI that are more
sensitive, more specific, and more convenient than the tuberculin skin test (7). Mononuclear cells from a single blood sample were stimulated with ESAT-6 peptides, and the ELISPOT
method was used to detect as few as 1 in 60,000 IFN-␥-producing cells. This test was positive in 96% of 47 tuberculosis patients and in 85% of 26 persons presumed to have LTBI, on
the basis of household contact with a patient with tuberculosis
and a positive Heaf test. Because the multiple-puncture Heaf
test yields more false-positive results than the intradermal
Mantoux test, some of these 26 persons may not have had
LTBI, and the sensitivity of the ELISPOT test may exceed
85%. The ELISPOT test was negative in 26 BCG-vaccinated
control subjects, and this specificity confers a major advantage
over tuberculin skin testing.
Most previous studies of the response to ESAT-6 have
used an enzyme-linked immunoassay (ELISA) to measure
IFN-␥ concentrations in supernatants of ESAT-6-stimulated
cells from patients with tuberculosis, with a sensitivity of 48%
in the largest study of 121 patients (2). The current report suggests that the ELISPOT method is more sensitive than the
ELISA for diagnosis of tuberculosis and of LTBI. In addition,
ELISPOT results can be obtained after 24 h, whereas the
ELISA measures IFN-␥ production by cells cultured for 5–6 d.
Further studies are needed to establish the sensitivity and
specificity of the ELISPOT test for LTBI in large populations.
Because most mycobacterial epitopes are recognized in the
context of specific HLA antigens, the ELISPOT test should be
evaluated at multiple geographic locations among patients of
different ethnicities. Although BCG vaccination does not yield
false-positive ELISPOT results (4, 7), the specificity of the
ELISPOT test should be studied in persons exposed to environmental mycobacteria such as M. avium complex. It may
now be possible to identify such persons by skin testing with
M. avium sensitin (8).
The ELISPOT test is not yet suitable for widespread use
because it is costly and requires isolation of mononuclear cells,
a procedure that is not performed in clinical laboratories.
These problems could be overcome through technological advances, such as the use of whole blood in the assay instead of
mononuclear cells (9), precoating ELISPOT plates with antibodies, reduced incubation times, and automated methods to
count the number of positive spots.
Although the ELISPOT test should greatly facilitate detection of LTBI, its role in diagnosing tuberculosis is more complex. In high-incidence countries where LTBI is common, a
positive ELISPOT test will not be specific for tuberculosis. In
low-incidence countries, the positive predictive value of the
test (probability that a patient with a positive test result has
tuberculosis) will also be low, even if the test is 99% sensitive
and 99% specific for LTBI and for tuberculosis. For example,
in the United States, if 1,000 patients with suspected tuberculosis are tested, approximately 200 will have tuberculosis and
800 will not, and approximately 15% (120) of the patients without tuberculosis will have LTBI. This estimate is higher than
the 5–10% prevalence of LTBI in the general population, as
would be anticipated among patients with suspected tuberculosis. Most patients with LTBI will have positive ELISPOT tests.
Therefore, among the 1,000 patients in whom the ELISPOT test
is performed, 198 tuberculosis patients and 126 patients without
tuberculosis will have positive tests, yielding a positive predictive value of only 61% [198/(198 ⫹ 126)].
Although a positive ELISPOT test is unlikely to confirm
the diagnosis of tuberculosis, the negative predictive value of
the test (probability that a patient with a negative test result
does not have tuberculosis) may be extremely high. For exam-
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ple, using the same test characteristics and population described above, 2 patients with tuberculosis and 674 patients
without tuberculosis will have negative ELISPOT tests, a negative predictive value of 99.7% [674/(674 ⫹ 2)], excluding tuberculosis with a high degree of confidence. The negative predictive value will be reduced if the sensitivity of the ELISPOT
test is significantly lower in patients with tuberculosis than in
those with LTBI, a realistic possibility because M. tuberculosis-induced IFN-␥ production by blood mononuclear cells is
decreased in patients with tuberculosis, particularly in those
with severe disease (2, 10). Studies of larger numbers of patients with tuberculosis are needed to address this issue.
In summary, the article by Lalvani and coworkers represents a major advance in the quest for better tests to diagnose
LTBI. The microbial genomics explosion will yield more M.
tuberculosis-specific genes and antigens, and an ELISPOT test
using peptides from multiple antigens should be more sensitive than one using ESAT-6 alone. If this test can be adapted
for clinical use, I believe that it will replace tuberculin skin
testing and greatly facilitate the elimination of tuberculosis in
low-incidence countries.
PETER F. BARNES
Center for Pulmonary and Infectious Disease Control
and Departments of Cell Biology, and Medicine
University of Texas Health Center
Tyler, Texas
References
1. Pottumarthy S, Morris AJ, Harrison AC, Wells VC. Evaluation of the
tuberculin gamma interferon assay: potential to replace the Mantoux
skin test. J Clin Microbiol 1999;37:3229–3232.
2. Ravn P, Demissie A, Eguale T, Wondwosson H, Lein D, Amoudy HA,
Mustafa AS, Jensen AK, Holm A, Rosenkrands I, Oftung F, Olobo J,
von Reyn F, Andersen P. Human T cell responses to the ESAT-6 antigen from Mycobacterium tuberculosis. J Infect Dis 1999;179:637–645.
3. Arend SM, Andersen P, van Meijgaarden KE, Skjøt RLV, Subronto
YW, van Dissel JT, Ottenhoff THM. Detection of active tuberculosis
infection by T cell responses to early-secreted antigenic target 6-kDa
protein and culture filtrate protein 10. J Infect Dis 2000;181:1850–1854.
4. Lalvani A, Nagvenkar P, Udwadia Z, Pathan AA, Wilkinson KA, Shastri JS, Ewer K, Hill AVS, Mehta A, Rodrigues C. Enumeration of T
cells specific for RD1-encoded antigens suggests a high prevalence of
latent Mycobacterium tuberculosis infection in healthy urban Indians.
J Infect Dis 2001;183:469–477.
5. Ulrichs T, Munk ME, Mollenkopf H, Behr-Perst S, Colangeli R,
Gennaro ML, Kaufmann HE. Differential T cell responses to Mycobacterium tuberculosis ESAT6 in tuberculosis patients and healthy donors. Eur J Immunol 1998;28:3949–3958.
6. Lalvani A, Brookes R, Wilkinson R, Malin A, Pathan A, Andersen P,
Dockrell H, Pasvol G, Hill A. Human cytolytic and interferon
gamma-secreting CD8⫹ T lymphocytes specific for Mycobacterium tuberculosis. Proc Natl Acad Sci USA 1998;95:270–275.
7. Lalvani A, Pathan AA, McShane H, Wilkinson RJ, Larif M, Conlon CP,
Pasvol G, Hill AVS. Rapid detection of M. tuberculosis infection by
enumeration of antigen-specific cells. Am J Respir Crit Care Med
2001;824–828.
8. Vankayalapati R, Wizel B, Samten B, Griffith DE, Shams H, Galland
MR, von Reyn CF, Girard WM, Wallace RJ Jr, Barnes PF. Cytokine
profiles in immunocompetent persons infected with Mycobacterium
avium complex. J Infect Dis 2001;183:478–484.
9. Elliott AM, Hurst TJ, Balyeku MN, Quigley MA, Kaleebu P, French N,
Biryahwaho B, Whitworth JAG, Dockrell HM, Hayes RJ. The immune response to Mycobacterium tuberculosis in HIV-infected and
uninfected adults in Uganda: application of a whole blood cytokine assay in an epidemiological study. Int J Tuberc Lung Dis 1999;3:239–247.
10. Sodhi A, Gong J-H, Silva C, Qian D, Barnes PF. Clinical correlates of
interferon-gamma production in tuberculosis patients. Clin Infect Dis
1997;25:617–620.