Tuberculosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

Pathogenesis

90% of the immunocompetent persons who are infected with M. tuberculosis do not develop symptoms. In these cases, the bacteria may either be eliminated by the immune system, or be kept in the latent state.[1]

The bacteria reach the terminal airways of the lungs, commonly at the middle lobes, upper regions of lower lobes and lower regions of upper lobes, where they begin to replicate. The initial focus of infection in the lung is a single region in 75% of the cases, and is called Ghon focus. At this focus, M. tuberculosis will be phagocytosed by local macrophages and dendritic cells. Although the immune cells may be able to eliminate the bacteria, M. tuberculosis is often able to replicate and destroy these cells. Besides the alveolar macrophages, other immune cells, such as blood monocytes (tissue macrophages) and lymphocytes, migrate to the Ghon focus to phagocytose the newly formed bacteria. A focus of inflammation is created and pneumonitis occurs.[1][2]

In an immunocompetent person, the infected macrophages are transported through the lymph to the regional lymph nodes. In immunocompromised patients, these macrophages may reach different parts of the body, through the bloodstream. During the dissemination of the infected macrophages, tissues that are more prone to bacterial replication, represent potential metastatic foci. These tissues include:[1][2]

Although all parts of the body can be affected by TB, this rarely affects the heart, skeletal muscles, pancreas and thyroid.[3]

TB is a granulomatous inflammatory disease. The granuloma may contain the following cells:[4]

The granuloma prevents the dissemination of mycobacteria and provides a pathway for immune cell communication. Within the granuloma, T lymphocytes (CD4) secrete cytokines, such as interferon gamma, which activate local macrophages to kill the bacteria with which they are infected.[4]

Primary Infection

The result of the tuberculin test is positive after 3-9 weeks of the initial infection. The positivity of this test represents an hypersensitivity reaction, and the development of cellular immune response towards the M. tuberculosis. In most immunocompetent patients, the immune system is able to control the infection, and a positive TST result is the only sign of this reaction.[1]

In a small number of cases, when there is a large concentration of antigens in the primary focus, the development of the immune response and hypersensitivity may lead to the necrosis and calcification of this infection site. These primary calcified foci are called Ranke complex.[1][5]

Progression of the Primary Infection

Initial foci of infection may evolve into large pulmonary lymph nodes. These may lead to:[1]

More commonly in non-caucasian children, with inferior resistance to tuberculosis, the primary focus of infection may evolve to constitute progressive primary disease, with advancing pneumonia. The infection may lead to the formation of cavitations with spread of the infection through the bronchi. This may also occur in HIV and elderly patients.[1][6][7]

In young children, the dissemination of infection before the onset of hypersensitivity may lead to military tuberculosis. Bacteria may disseminate directly from the primary focus, or from the Weigart focus (metastatic focus adjacent to a pulmonary vein) through the blood.[1][8]

In younger patients, serofibrinous pleurisy is more prone to occur following the rupture of subpleural foci of infection into the pleural space.[1]

The most severe consequence of the dissemination of bacteria from primary or metastatic foci, through the blood and lymph, is the seeding of the postero-apical regions of the lung. Here bacteria are able to replicate without the opposition of the immune system, potentially leading pulmonary tuberculosis.[1]

Age Influence on Tuberculosis

Depending on the age of the patient, tuberculosis may have different clinical manifestations, progression, and prognosis:[1][6][9][10][11][9][12]

Factor Influence
Location

The location of tuberculosis in the lung is influenced by the age of the patient:

  • Adolescents and adult patients - predominance in the postero-apical region of the lung. This location is thought to be due to a deficient drainage of this region, thereby facilitating the retention of bacteria and necrosis.
  • Elderly patients - predominance of infection in the lower lobes
Infants and Children
  • Younger age (< 5 years) is associated with higher risk of developing progressive disease.
  • Infants are more prone to the development of tuberculosis following infection with M. tuberculosis.
  • Tendency for the disease to disseminate and evolve into miliary tuberculosis.
  • Common involvement of:
  • Good prognosis, even in the absence of treatment, often with spontaneous healing.
  • Cavitary tuberculosis has an higher risk of relapse.
Adolescents
  • Commonly affects lower regions of the lungs and presents with hilar adenitis
  • Hilar calcification is rare
  • Common in immunocompromised and dark-skinned patients
  • Towards young adulthood, the disease tends to occur in apical regions.
Midadulthood
  • If infection is acquired during mid adulthood, the disease has a better prognosis, possibly due to the existence of less necrotic tissue.
Elderly
  • Elderly patients have a weaker immune system. Therefore, latent disease, acquired at younger ages, may progress into active tuberculosis with postero-apical predominance.
  • A large group of elderly patients are TST negative because: they have never been infected; they have lost the hypersensitivity reaction; or because they have completely cleared previous infections. These patients are susceptible of reinfection.
  • Tuberculosis in these patients often presents as lower or middle lobe pneumonitis, seldom with pleural effusion.
  • Similar to childhood tuberculosis, with less degree of lymphadenopathy
  • Higher death rate

Immune Response

The immune response against M. tuberculosis has a great involvement from cellular immunity.[13] Despite the humural response during tuberculosis with production of numerous antibodies, its role in the immune response towards the bacteria is not defined. The immune response against M. tuberculosis is minimal during the first weeks, allowing it to replicate in the alveolar spaces and macrophages, constituting the Ghon focus, or metastatic foci. Bacterial entrance intro the macrophages occurs by interaction with the following receptors:[14]

Once within alveolar macrophages, M. tuberculosis uses multiple mechanisms in order to survive:[15]

  • Within the lysosome, the bacteria do not induce CD8 response

Alveolar macrophages and dendritic cells present mycobacterial antigens on their surfaces through class II major histocompatibility complex. These antigens will be recognized by CD4 lymphocytes through αβ T-cell receptors. CD4 lymphocytes, once activated, release lymphokines that attract more macrophages to the site of infection. During lymphocyte activation, immune cells produce large amounts of lytic enzymes, which when released, lead to the necrosis of tissues. Macrophages will also stimulate epithelioid cells, that will be responsible for the formation of the granuloma.[16]

About 3-9 weeks after infection with M. tuberculosis, the immune response reaches a level that is manifested by a positive TST result. The concentration of mycobacterial antigens and the level of the immune response are responsible for the clinical manifestations of tuberculosis.[17]

A granuloma is formed in the presence of a low antigen load, with a hypersensitive tissue response, that is manifested by a large accumulation of host cells, such as:[18]

In the presence of a high antigen load, with a hypersensitive tissue response, immune cells are not properly organized, and necrotic tissue may be formed.[19]

When the reaction of the immune system is successful, the healing process lead to the formation of a scar, on the fibrotic and encapsulated tissue (exudative reaction). If necrosis is incomplete, a caseous material may be formed. If the caseous material is discharged through the bronchial airways, tuberculous cavities may be formed, which may be co-infected by multiple bacteria. In the absence of necrosis, full healing may occur.[20]

If the immune response is weak, nonreactive tuberculosis may be noted. In this case unspecific tissue changes may be noted, with few immune cells surrounding large amounts of bacilli.[21]

In persons with a tuberculin-positive test, endogenous foci of the bacteria may be reactivated. CD4 lymphocytes are responsible for inhibiting this reactivation.[22]

Transmission

After contact with an infected patient, with the active form of the disease, and inhalation of M. tuberculosis the risk of developing active tuberculosis is low, with a life-time projected risk of about 10%.[23] The probability of transmission from one person to another depends upon the number of infectious droplets expelled by a carrier, the effectiveness of ventilation, the duration of exposure, and the virulence of the M. tuberculosis strain.[24] The probability of transmitting the disease is highest during the first years after infection, decreasing thenceforth.[25]

In rare occasions, the bacteria may be transmitted through other ways, besides the pulmonary route. In these cases, the formation of foci in local lymph nodes is always involved. These routes of transmission include:[26]

Associated Conditions

AIDS

Tuberculosis influences the progression of HIV replication in infected patients, leading to an increase in the mortality rate.[27]

On the other hand, HIV infected patients, particularly those with low counts of CD4 lymphocytes have increased risk of reactivation of latent tuberculosis. Additionally, when recently infected with M. tuberculosis, these patients tend to rapidly progress into active tuberculosis.[28][29][30] It is still not known if AIDS influences the risk of infection, when in contact with the M. tuberculosis.[31]

Patients with AIDS have increased risk of developing pulmonary and extrapulmonary tuberculosis. Since 1992, this concomitant disease manifestation in AIDS patients has declined considerably.[32] Extrapulmonary disease in this group of patients has characteristic manifestations, such as:[33]

Gallery

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  2. ↑ 2.0 2.1 Herrmann J, Lagrange P (2005). "Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse?". Pathol Biol (Paris). 53 (1): 35–40. PMID 15620608.
  3. ↑ Agarwal R, Malhotra P, Awasthi A, Kakkar N, Gupta D (2005). "Tuberculous dilated cardiomyopathy: an under-recognized entity?". BMC Infect Dis. 5 (1): 29. PMID 15857515.
  4. ↑ 4.0 4.1 Kaufmann S (2002). "Protection against tuberculosis: cytokines, T cells, and macrophages". Ann Rheum Dis. 61 Suppl 2: ii54–8. PMID 12379623.
  5. ↑ Grosset J (2003). "Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary". Antimicrob Agents Chemother. 47 (3): 833–6. PMID 12604509.
  6. ↑ 6.0 6.1 Stead WW, Lofgren JP, Warren E, Thomas C (1985). "Tuberculosis as an endemic and nosocomial infection among the elderly in nursing homes". N Engl J Med. 312 (23): 1483–7. doi:10.1056/NEJM198506063122304. PMID 3990748.
  7. ↑ Murray JF (1990). "Cursed duet: HIV infection and tuberculosis". Respiration. 57 (3): 210–20. PMID 2274719.
  8. ↑ Kim J, Park Y, Kim Y, Kang S, Shin J, Park I, Choi B (2003). "Miliary tuberculosis and acute respiratory distress syndrome". Int J Tuberc Lung Dis. 7 (4): 359–64. PMID 12733492.
  9. ↑ 9.0 9.1 DAHL RH (1952). "[The first appearance of a pulmonary cavity after primary infection with relation to time and age]". Acta Tuberc Scand. 27 (1–2): 140–9. PMID 13007533.
  10. ↑ Stead WW (1967). "Pathogenesis of a first episode of chronic pulmonary tuberculosis in man: recrudescence of residuals of the primary infection or exogenous reinfection?". Am Rev Respir Dis. 95 (5): 729–45. PMID 4960690.
  11. ↑ "Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement". Am J Respir Crit Care Med. 161 (4 Pt 2): S221–47. 2000. doi:10.1164/ajrccm.161.supplement_3.ats600. PMID 10764341.
  12. ↑ Stead WW, Kerby GR, Schlueter DP, Jordahl CW (1968). "The clinical spectrum of primary tuberculosis in adults. Confusion with reinfection in the pathogenesis of chronic tuberculosis". Ann Intern Med. 68 (4): 731–45. PMID 5642961.
  13. ↑ Orme IM, Andersen P, Boom WH (1993). "T cell response to Mycobacterium tuberculosis". J Infect Dis. 167 (6): 1481–97. PMID 8501346.
  14. ↑ Aderem A, Underhill DM (1999). "Mechanisms of phagocytosis in macrophages". Annu Rev Immunol. 17: 593–623. doi:10.1146/annurev.immunol.17.1.593. PMID 10358769.
  15. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  16. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  17. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  18. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  19. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  20. ↑ Canetti G (1965). "Present aspects of bacterial resistance in tuberculosis". Am Rev Respir Dis. 92 (5): 687–703. PMID 5321145.
  21. ↑ O'BRIEN JR (1954). "Non-reactive tuberculosis". J Clin Pathol. 7 (3): 216–25. PMC 1023795. PMID 13192197.
  22. ↑ Ellner JJ (1997). "Review: the immune response in human tuberculosis--implications for tuberculosis control". J Infect Dis. 176 (5): 1351–9. PMID 9359738.
  23. ↑ Glaziou P, Falzon D, Floyd K, Raviglione M (2013). "Global epidemiology of tuberculosis". Semin Respir Crit Care Med. 34 (1): 3–16. doi:10.1055/s-0032-1333467. PMID 23460002.
  24. ↑ "Causes of Tuberculosis". Mayo Clinic. 2006-12-21. Retrieved 2007-10-19.
  25. ↑ Lawn SD, Zumla AI (2011). "Tuberculosis". Lancet. 378 (9785): 57–72. doi:10.1016/S0140-6736(10)62173-3. PMID 21420161.
  26. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  27. ↑ Zumla A, Raviglione M, Hafner R, von Reyn CF (2013). "Tuberculosis". N Engl J Med. 368 (8): 745–55. doi:10.1056/NEJMra1200894. PMID 23425167.
  28. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  29. ↑ Daley CL, Small PM, Schecter GF, Schoolnik GK, McAdam RA, Jacobs WR; et al. (1992). "An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragment-length polymorphisms". N Engl J Med. 326 (4): 231–5. doi:10.1056/NEJM199201233260404. PMID 1345800.
  30. ↑ Bouvet E, Casalino E, Mendoza-Sassi G, Lariven S, Vallée E, Pernet M; et al. (1993). "A nosocomial outbreak of multidrug-resistant Mycobacterium bovis among HIV-infected patients. A case-control study". AIDS. 7 (11): 1453–60. PMID 8280411.
  31. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  32. ↑ "Tuberculosis Morbidity -- United States, 1997". MMWR.
  33. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  34. ↑ Shafer RW, Kim DS, Weiss JP, Quale JM (1991). "Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection". Medicine (Baltimore). 70 (6): 384–97. PMID 1956280.
  35. ↑ Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W; et al. (2008). "Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings". Lancet Infect Dis. 8 (8): 516–23. doi:10.1016/S1473-3099(08)70184-1. PMC 2804035. PMID 18652998.
  36. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  37. ↑ 37.0 37.1 37.2 37.3 37.4 37.5 37.6 37.7 37.8 "Public Health Image Library (PHIL), Centers for Disease Control and Prevention".

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