Diagnosis: Active tuberculosis, superior segment of left lower lobe

Comment: This patient, a 76-year-old smoker who grew up in China, had a lung mass, for which no diagnosis could be made despite an extensive work-up. Excision of the mass showed infection with M. tuberculosis. In retrospect, the needle biopsy showing evidence of granuloma indicated the correct diagnosis, but the organism did not grow on culture of that material. Further, granulomas may sometimes be a prominent reaction to neoplasm. Some doubt about the negative tuberculin skin test was raised as it was not performed at this institution. The location of the lesion in the superior segment of the lower lobe suggests that it represents postprimary tuberculosis. The low-grade hilar uptake on the PET scan may represent increased metabolic activity due to reactive lymphadenopathy. Enlarged lymph nodes with central low attenuation, not seen in this case, would be expected in active tuberculous lymphadenitis. In summary, this case illustrates the difficulty sometimes encountered in distinguishing infection from neoplasm.


Tuberculosis

Introduction: Tuberculosis causes more deaths than any other infectious disease. An estimated one third of the world's population is infected with the organism, which thrives in patients who are malnourished or immunosuppressed. In the U.S., incidence of the disease, which declined until 1985 (9.3 cases/100,000), increased until 1992 (10.5/100,000) because of a combination of factors including the prevalence of HIV infection, increased homelessness and intravenous drug use, and the decline in tuberculosis treatment programs, and then fell in 1999 to 6.4/100,000 (click on surveillance report 1999) as money was raised to combat the problem. Currently, measures to combat the disease are aimed at education of the medical profession in the treatment of the disease and at use of directly observed short course therapy (DOTS), which seeks to prevent transmission and emergence of drug-resistant organisms [1]

Epidemiology: Populations at risk include immigrants from countries with high rates of tuberculosis, AIDS patients, and persons living in homeless shelters and nursing homes [1]. Other groups at risk are close contacts, infants, young adults, and those with hematologic malignancies, silicosis, gastrectomy, or alcoholism [2]. About 5% of cases of tuberculosis in the U.S. are diagnosed only at death, and this figure may be low because the rate of postmortem examination in hospital has declined to 15% overall. Most of the patients diagnosed postmortem are over age 65 or have miliary, meningeal, or peritoneal tuberculosis [3].

Recent epidemiologic studies of the transmission of tuberculosis in urban areas have found that the assumption that only 10% of cases result from recent infection (90% from reactivation) is no longer universally valid. In studies from San Francisco and New York City, DNA fingerprinting of isolated organisms by restriction-fragment-length polymorphism (RFLP) was used to identify organisms of the same strain, presumably from a common source. Using this technique, 30-40% of newly-diagnosed cases occurred in clusters of 2 or more people with the same strain, suggesting recent transmission and progression to disease. Factors associated with being in a cluster for patients under 60 years old were Hispanic ethnicity, black race, birth in the U.S., and AIDS. Tracing of persons in the same cluster indicated that the disease could be transmitted by brief contact between persons who did not live or work together. The studies also suggested that traditional tracing of contacts was incomplete [4,5]. Further, a study of relapses of tuberculosis after curative therapy showed by RFLP that 12 of 16 patients (probably all HIV-1 negative) from an area in South Africa endemic for tuberculosis were infected by a new strain [6]. Because of these findings, directly observed short-course therapy and prompt case detection have emerged as major public health measures in combatting the disease.

Pathogenesis: Tuberculosis is acquired by inhalation of aerosolized microdroplets, <5 µm in diameter, into the alveoli. The primary lesion is usually in the mid to lower lung parenchyma because ventilation is greatest there. After several weeks, a granulomatous response occurs locally signifying the development of sensitized T cells (delayed type hypersensitivity (DTH)) and immunity (cell-mediated immunity (CMI)) [7].

In the meantime, bacilli have also spread lymphogenously to hilar lymph nodes and hematogenously to the rest of the body, being cleared by reticuloendothelial cells of adrenals, liver, bone marrow, and spleen. Bacilli also spread hematogenously throughout the lung. All of these organisms are usually killed or subdued by the immunocompetent host. Bacilli deposited at the apices of the lung often persist long enough to cause scarring, perhaps because host defenses related to lymphatic clearance and blood perfusion are less there than in other parts of the lung [8]. Because of this early hematogenous dissemination, postprimary, reactivation tuberculosis can occur at almost any site in the body. Usually, a period of latent, inactive infection follows [7].

In the immunocompetent host, postprimary (or reinfection) disease usually presents as a progressive, cavitating pneumonia with endobronchial spread. In the immunocompromised host, primary, postprimary, or reinfection pulmonary disease can present as a progressive (often non-cavitating) pneumonia with endobronchial spread, or it can erode into a vein and produce dissemination throughout the body in a miliary pattern (small granulomas all at the same stage of development) [7].

Clinical features: Symptoms, which include fever, night sweats, weight loss, hematologic abnormalities, cough, pleurisy, dyspnea, and hemoptysis, are non-specific. Diagnosis requires isolation of the organism.

Tuberculosis in AIDS: Tuberculosis is an AIDS-defining disease for HIV-positive persons and is often the first opportunistic pulmonary infection. A positive skin test with purified protein derivative in an HIV-positive person confers a risk of developing tuberculosis of 5-10% a year. In contrast, an HIV-negative, immunocompetent person with a positive test has a risk of tuberculosis of 10% over a lifetime [9]. The clinical presentation in AIDS depends on the degree of immunosuppression as indicated by the CD4 T-cell count. Patients with CD4 counts >200/µl have presentations similar to HIV-negative persons. In patients with CD4 counts <200 cells/µl, however, cavitary disease is less common and the following characteristics are more frequent than in those with >200 CD4 cells/µl [10].

Radiographic patterns: In immunocompetent adults, the typical pattern of primary disease, usually in children, is an opacity in mid or lower lung fields, with hilar or mediastinal adenopathy. Pleural effusions, miliary disease, or a normal radiograph can be encountered. Postprimary tuberculosis presents as an opacity in the apical or posterior segments of the upper lobes or superior segment of the lower lobe ± cavitation. Isolated involvement of the anterior segment of the upper lobe is extremely rare. Adenopathy is unusual [11]. The plain film underestimates the extent of lung involvement [12].

In AIDS patients, a typical pattern is expected in patients with CD4 counts >200 cells/µl. Atypical patterns tend to occur with lower counts. These patterns include [11]:

CT patterns in non-HIV patients: CT patterns have been described in postprimary tuberculosis. These patterns have been divided into those representing active, and those representing healed, fibrotic, disease. As a result of studying patients with active disease, as well as patients after therapy, the authors of one study concluded that endobronchial spread of disease was the rule and was manifested by centrilobular nodules, branching structures, and macronodules, which occurred in all patients except those with miliary disease. These changes mostly cleared with therapy. Patterns associated with endobronchial spread and other changes of active disease are listed and correlated with histologic changes in Table 1. Changes found after completion of therapy are listed in Table 2 [12].

Look at the CT and the list of changes in active, postprimary disease listed below. Match the numbers with the best description.

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2.

3.

4.

5.

Table 1. Correlation of CT and Histologic Changes in Active, Postprimary Tuberculosis [12]

CT changes indicating activity [12,14,15]

Corresponding histologic changes (see below for descriptions)

Focal consolidation ± central cavity ± surrounding ground-glass opacities

Confluent granulomatous inflammation

Centrilobular nodule, 2-4 mm in diameter

Involvement of terminal or respiratory bronchioles and adjacent alveolar spaces

Multiple, fine, branching structures from a single stalk--"tree-in-bud" pattern

Involvement of distal bronchiole (stalk) and several acinar branches

Macronodules, 5-8 mm in diameter

Confluent peribronchiolar nodules with intra-acinar spread

Bronchial wall thickening and lumenal dilation

Granulomatous inflammatory bronchiectasis

Mosaic pattern of reduced lung attenuation

Bronchiolar and vascular narrowing produce acinar oligemia and overinflation (probably not recognized in histologic sections)

Mediastinal lymph node enlargement

Granulomas in lymph nodes

Bronchial impaction: thick, branching, linear structures

Exudate in bronchi

Miliary pattern

Multiple, randomly-oriented, small granulomas

Pleural effusion

Table 2: Changes of healed, fibrotic disease [12]

Functional correlates of the CT changes [12]: Twenty-five patients with tuberculosis, who had no underlying lung disease, were studied prospectively to correlate pulmonary function with CT findings. When extent of active disease was measured by number of involved pulmonary segments, FEV1 and FVC declined as the number of segments involved increased. Mild, fixed obstruction sometimes developed after therapy; rarely, obstruction progressed with time. Patients with cavitary disease had involvement of more pulmonary segments than those with non-cavitary disease. Finally, abnormalities of ventilation (endobronchial disease) and perfusion (endarteritis obliterans) tended to decline in parallel.

The differential diagnosis of the varied radiographic appearances includes pyogenic bacterial pneumonias, fungal pneumonias, nontuberculous mycobacterial infections, sarcoidosis, and cancer.

Pathologic patterns--gross features: Typical gross patterns are listed below with links to further description. All except the first, which characterizes primary infection, may be found in primary or postprimary disease. Note, by clicking on the first item, you may go directly through the list before returning to the discussion.

Histologic features--summary

Molecular Pathogenic Mechanisms in the Development of M. tuberculosis: An outline of a few of the complex molecular steps in the development of disease is given below [16].

Molecular Events

Results or Manifestations

Binding of M. tuberculosis by macrophages via complement receptors, mannose receptors, and CD14 (which also binds bacterial lipopolysaccharide).

Phagocytosis of organisms initiates delayed type hypersensitivity and cell mediated immunity

Uptake into phagocytic vacuole

Organisms grow in vacuole and tend to inhibit fusion with lysosomes that contain bactericidal products.

Phagocytes release chemokines that recruit monocytes, PMNs, and T cells

Patients with active pulmonary tuberculosis have more chemokines--RANTES, MCP-1, and IL-8*--in lavage fluid than control patients [17]

Interaction of T cells with infected macrophages induces production of macrophage cytokines--TNF-alfa, IFN-gamma, TGF-beta**, & others

Patients with active tuberculosis have T cells in lavage fluid that are producing more IFN-gamma than T cells of control patients [18].

*RANTES = Regulated on activation, normal T cell expressed and secreted, MCP-1 = monocyte chemotactic protein-1, Il-8 = interleukin-8

** TNF = tumor necrosis factor, IFN = interferon, TGF = transforming growth factor

Macrophage and T-cell Interactions in Tuberculosis [16]

Diagram:

  • After phagocytosis of tubercle bacilli, macrophages secrete chemokines that attract leukocytes. Interaction with lymphocytes stimulates macrophages to produce IFN-gamma and TNF-alfa, thereby activating CD4 + T lymphocytes.
  • These lymphocytes produce cytokines, IL-2 and IFN-gamma, which activate macrophages and other lymphocytes.
  • Cytolytic T cells (see below) and macrophage-produced, lysosomal, reactive nitrogen and oxygen intermediates participate in bacterial killing [19].
  • In mice, the presence of TNF-alfa and IFN-gamma are both important early in infection for good granuloma formation and control of infection [20,21].
  • TGF-beta, on the other hand, tends to dampen the immune responses and to cause tissue destruction and fibrosis (see below). This interplay of cytokines is important in determining the outcome of infection [22].
  • In the process of macrophage activation, the cell develops more cytoplasm (becomes epithelioid), loses its phagocytic ability, and assumes a secretory role in the production of cytokines.

 

 

Bacterial killing: An immune mechanism for killing the organisms has recently been discovered in cultured human cells [19]. CD8+ cytolytic T lymphocytes (CTLs) that were sensitized to M. tuberculosis were shown to contain in cytoplasmic granules a protein, granulysin, that kills free organisms. However, granulysin had no activity against organisms in macrophages. Another protein, perforin, also found in the granules of CTLs, caused lysis of alveolar macrophages, and together they resulted in killing of intracellular organisms. This immune-mediated T cell activity--the perforin-granulysin microbicidal pathway, complements the effects of reactive nitrogen and oxygen intermediates.

Role of transforming growth factor-beta (TGF-beta): M. tuberculosis has adjuvant properties that should enhance the immune response, and yet it tends to suppress T-cell mediated responses. In cultured human cells, one of the mechanisms of suppression of T-cells is production by activated macrophages of TGF-beta, which acts on the immune response in a number of ways outlined below [22]:

Thus, M. tuberculosis stimulates the macrophage to produce TGF-beta, which inhibits macrophage killing, causes tissue damage, and suppresses T cell responses. Neutralization of TGF-beta prevents some of these effects in patients with active tuberculosis [22].

Conclusions: Many cytokines are involved in regulating bacterial killing, the inflammatory response, and immunostimulation or suppression in the normal host. These interactions generally favor the bacillus, even if it must remain dormant for long periods. Anti-tuberculous drugs tip the balance in favor of the host.

References

1. Bloom B, Murray C. Tuberculosis: commentary on a reemergent killer. Science 1992; 257:1055-1064.

2. Hopewell P, Bloom B. Tuberculosis and other mycobacterial diseases. In: Textbook of Respiratory Medicine. JF Murray, JA Nadel (eds): 2nd edition, Philadelphia, Saunders, 1994:1094-1160.

3. Rieder H, Kelly G, Bloch A, Cauthen G, Snider Jr D. Tuberculosis diagnosed at death in the United States. Chest 1991; 100:678-681.

4. Alland D, Kalkut G, Moss A, McAdam R, Hahn J, Bosworth W, Drucker E, et al. Transmission of tuberculosis in New York City. An analysis by DNA fingerprinting and conventional epidemiologic methods. N Engl J Med 1994; 330:1710-1716.

5. Small P, Hopewell P, Singh S, Paz A, Parsonnet J, Ruston D, Schecter G, et al. The epidemiology of tuberculosis in San Francisco. A population-based study using conventional and molecular methods. N Engl J Med 1994; 330:1703-1709.

6. van Rie A, Warren R, Richardson M, Victor T, Gie R, Enarson D, Beyers N, et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 1999; 341:1174-1179.

7. Geppert E, Leff A. The pathogenesis of pulmonary and miliary tuberculosis. Arch Intern Med 1979; 139:1381-1383.

8. Goodwin R, Des Prez R. Apical localization of pulmonary tuberculosis, chronic pulmonary histoplasmosis, and progressive massive fibrosis of the lung. Chest 1983; 83:801-805.

9. Daley C. Current issues in the pathogenesis and management of HIV-related tuberculosis. AIDS Clin Review 1997-1998:289-321.

10. Jones B, Young S, Antoniskis D, Davidson P, Kramer F, Barnes P. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 1993; 148:1292-1297.

11. Keiper M, Beumont M, Elshami A, Langlotz C, Miller Jr W. CD4 T lymphocyte count and the radiographic presentation of pulmonary tuberculosis. A study of the relationship between these factors in patients with human immunodeficiency virus infection. Chest 1995; 107:74-80.

12. Long R, Maycher B, Dhar A, Manfreda J, Hershfield E, Anthonisen N. Pulmonary tuberculosis treated with directly observed therapy. Serial changes in lung structure and function. Chest 1998; 113:933-943.

13. Pastores S, Naidich D, Aranda C, McGuinnes G, Rom W. Intrathoracic adenopathy associated with pulmonary tuberculosis in patients with human immunodeficiency virus infection. Chest 1993; 103:1433-1437.

14. Im J-G, Itoh H, Shim Y-S, Lee J, Ahn J, Han M, Noma S. Pulmonary tuberculosis: CT findings--early active disease and sequential change with antituberculous therapy. Radiology 1993; 186:653-660.

15. Hatipoglu O, Osma E, Manisali M, Ucan E, Balci P, Akkoclu A, Akpinar O, et al. High resolution computed tomographic findings in pulmonary tuberculosis. Thorax 1996; 51:397-402.

16. Fenton M, Vermeulen M. Immunopathology of tuberculosis: roles of macrophages and monocytes. Infect Immun 1996; 64:683-690.

17. Sadek M, Sada E, Toossi Z, Schwander S, Rich E. Chemokines induced by infection of mononuclear phagocytes with mycobacteria and present in lung alveoli during active pulmonary tuberculosis. Am J Respir Cell Mol Biol 1998; 19:513-521.

18. Robinson D, Ying S, Taylor I, Wangoo A, Mitchell D, Kay A, Hamid Q, et al. Evidence for a Th1-like bronchoalveolar T-cell subset and predominance of interferon-gamma gene activation in pulmonary tuberculosis. Am J Resir Crit Care Med 1994; 149:989-993.

19. Stenger S, Hanson D, Teitelbaum R, Dewan P, Niazi K, Froelich C, Ganz T, et al. An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 1998; 282:121-125.

20. Flynn J, Goldstein M, Chan J, Triebold K, Pfeffer K, Lowenstein C, Schreiber R, et al. Tumor necrosis factor-alfa is required in the protective immune reponse against Mycobacterium tuberculosis in mice. Immunity 1995; 2:561-572.

21. Caruso A, Serbina N, Klein E, Triebold K, Bloom B, Flynn J. Mice deficient in CD4 T cells have only transiently diminished levels of IFN-gamma, yet succumb to tuberculosis. J Immunol 1999; 162:5407-5416.

22. Toossi Z, Ellner J. The role of TGF-beta in the pathogenesis of human tuberculosis. Clin Immunol Immunopathol 1998; 87:107-114.

Clinical summary

Comments: mw6825@itsa.ucsf.edu

Table of Contents

Last revised 2/10/00

Copyright 2000 by Martha L. Warnock. All rights reserved.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1. Focal consolidation ± central cavity ± surrounding ground-glass opacities

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2. Bronchial wall thickening and lumenal dilation

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3. Multiple fine branching structures from a single stalk--"tree-in-bud" pattern

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4. Centrilobular nodule, 2-4 mm in diameter

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5. Bronchial impaction: thick, branching, linear structures

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