Tuberculosis pathophysiology: Difference between revisions

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{{Tuberculosis}}
{{Tuberculosis}}
{{CMG}}; {{AE}} {{JS}}
{{CMG}}; {{AE}} {{Mashal Awais}}, {{JS}}


==Overview==
==Overview==
[[Transmission (medicine)|Transmission]] of ''M. [[tuberculosis]]'' occurs when individuals with active [[Lung|pulmonary]] disease [[cough]], [[speak]], [[sneeze]] or sing [[expelling]] the [[Infection|infectious]] [[droplets]]. The [[mycobacterium]] [[tuberculosis]] favors the upper [[lung]] [[Lobe (anatomy)|lobes]] due to the high [[oxygen]] level. [[Tuberculosis]] is a prototypical [[Granuloma|granulomatous]] infection. The [[granuloma]] surrounds the [[Mycobacterium|mycobacteria]] and prevents their [[dissemination]] and facilitates the [[immune cell]] interaction.  Within the [[granuloma]], [[CD4|CD4 T lymphocytes]] release [[Chemokine|chemokines]] that activate local [[macrophages]] and [[Recruitment status|recruit]] other [[Immunity (medical)|immune]] cells..


==Pathogenesis==
==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.<ref name="Mandell">{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>   
[[Transmission (medicine)|Transmission]] of ''M. [[tuberculosis]]'' occurs when individuals with active [[Lung|pulmonary]] disease [[cough]], [[speak]], [[sneeze]] or sing [[expelling]] the [[Infection|infectious]] [[droplets]] that can pass to the terminal [[Bronchiole|bronchioles]] and [[Pulmonary alveolus|alveoli]] then [[Phagocytosis|phagocytosed]] by [[Alveolus|alveolar]] [[Macrophage|macrophages]] where they can [[replicate]] in the [[Endosome|endosomes]] of [[Alveolus|alveolar]] [[Macrophage|macrophages]]. As a part of the [[Immunity (medical)|immune]] response  by these [[Macrophage|macrophages]], the [[Alveolus|alveolar]] [[Macrophage|macrophages]] [[Release (information centre)|release]] [[Cytokine|cytokines]] that [[recruits]] further [[Macrophage|macrophages]], [[Neutrophil|neutrophils]], and [[Monocyte|monocytes]], surrounding the [[bacilli]]. Despite having a very low [[Infection|infectious]] dose (ID<200 bacteria), 90% of the infected [[Immunocompetence|immunocompetent]] individuals are [[Asymptomatic condition|asymptomatic]].  In most cases, the bacteria may either be eliminated or enclosed within a [[granuloma]].  The [[granuloma]] is a structured, radial [[aggregation]] of [[Macrophage|macrophages]], [[epithelioid]] cells, T [[Lymphocyte|lymphocytes]], B [[Lymphocyte|lymphocytes]], and [[Fibroblast|fibroblasts]] that prevents the [[Spreading activation|spreading]] of [[M. tuberculosis|mycobacteria]] and enhances interaction of the [[Immunity (medical)|immune]] cells.<ref name="Mandell">{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>  The primary site of [[infection]] in the [[lung]] is called the [[Ghon focus]] that is mainly located in either the upper part of the lower [[Lobe (anatomy)|lobe]], or the lower part of the upper [[Lobe (anatomy)|lobe]].<ref name="Mandell"></ref><ref name="Herrmann_2005">{{cite journal |author=Herrmann J, Lagrange P |title=Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse? |journal=Pathol Biol (Paris) |volume=53 |issue=1 |pages=35–40 |year=2005 | pmid = 15620608}}</ref>
 
===Primary Infection===
The infected [[macrophages]] are transported through the [[lymph|lymphatics]] to the regional [[lymph nodes]] in the [[Immunocompetence|immunocompetent]] individuals. However, with impaired immune response, these [[macrophages]] can pass through the [[Blood|bloodstream]] to enter any part of the body. Those foci of primary infection usually resolve without any consequences, but they can act as a foci of M. [[tuberculosis]] [[dissemination]].  There are particular organs that are more susceptible to [[Bacteria|bacterial]] [[replication]] as well as being potential [[Metastasis|metastatic]] foci which include:<ref name="Mandell"></ref><ref name="Herrmann_2005">{{cite journal |author=Herrmann J, Lagrange P |title=Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse? |journal=Pathol Biol (Paris) |volume=53 |issue=1 |pages=35–40 |year=2005 | pmid = 15620608}}</ref>
 
*Apical-posterior regions of the [[Lung|lungs]]
*[[Lymph nodes]]
*[[Kidneys]]
*[[Vertebral bodies]]
*[[Limb (anatomy)|Extremities]] of long [[bones]]
*Juxta [[Ependymal cell|ependymal]] [[meningeal]] regions
 
Although [[Tuberculosis|TB]] is a [[systemic]] disease and all [[Organ (anatomy)|organs]] can be affected, the [[heart]], [[pancreas]], [[skeletal muscle]]s and [[thyroid]] are rarely involved.<ref>{{cite journal |author=Agarwal R, Malhotra P, Awasthi A, Kakkar N, Gupta D |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15857515 |title=Tuberculous dilated cardiomyopathy: an under-recognized entity? |journal=BMC Infect Dis |volume=5 |issue=1 |pages=29 |year=2005 |pmid=15857515}}</ref> In a few cases, when the [[Infection|infectious]] [[dose]] is high and [[antigens]] concentration in the primary focus is high, the [[immune response]] and [[hypersensitivity]] can lead to [[necrosis]] and [[calcification]] of this lesion, and these primary [[Calcification|calcified]] foci are then called '''Ranke complex'''.<ref name="Mandell"></ref><ref name="Grosset">{{cite journal |author=Grosset J |title=Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary |journal=Antimicrob Agents Chemother |volume=47 |issue=3 |pages=833-6 |year=2003 | pmid = 12604509}}</ref>
 
===Progression of the Primary Infection===
Primary foci of [[infection]] can enter the large [[pulmonary]] [[lymph nodes]].  These may lead to:<ref name="Mandell"></ref>
 
*[[Bronchial]] [[Collapse (medical)|collapse]]
*[[atelectasis]]
*[[bronchus|Bronchial]] [[Erosion (dental)|erosion]], with more [[dissemination]] of [[infection]]


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 cell]]s.  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.<ref name="Mandell"></ref><ref name=Herrmann_2005>{{cite journal |author=Herrmann J, Lagrange P |title=Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse? |journal=Pathol Biol (Paris) |volume=53 |issue=1 |pages=35–40 |year=2005 | pmid = 15620608}}</ref>
*In non-caucasian children, [[Old age|elderly]] patients and [[Human Immunodeficiency Virus (HIV)|HIV]]/[[HIV AIDS|AIDS]], the [[Immunity (medical)|immune]] response is impaired, consequently the primary focus of infection can deteriorate into progressive primary disease, with advancing [[pneumonia]].


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:<ref name="Mandell"></ref><ref name=Herrmann_2005>{{cite journal |author=Herrmann J, Lagrange P |title=Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse? |journal=Pathol Biol (Paris) |volume=53 |issue=1 |pages=35–40 |year=2005 | pmid = 15620608}}</ref>
*In addition,the infection may result in [[cavity]] formation with [[Transmission (medicine)|transmission]] of the infection through the [[bronchi]].<ref name="Mandell"></ref><ref name="pmid3990748">{{cite journal| author=Stead WW, Lofgren JP, Warren E, Thomas C| title=Tuberculosis as an endemic and nosocomial infection among the elderly in nursing homes. | journal=N Engl J Med | year= 1985 | volume= 312 | issue= 23 | pages= 1483-7 | pmid=3990748 | doi=10.1056/NEJM198506063122304 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3990748  }} </ref><ref name="pmid2274719">{{cite journal| author=Murray JF| title=Cursed duet: HIV infection and tuberculosis. | journal=Respiration | year= 1990 | volume= 57 | issue= 3 | pages= 210-20 | pmid=2274719 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2274719  }} </ref>
* Apical-posterior regions of the lungs
* [[Lymph nodes]]
* [[Kidneys]]
* [[Vertebral bodies]]
* Extremities of long bones
* Juxtaependymal [[meningeal]] regions


Although all parts of the body can be affected by TB, this rarely affects the [[heart]], [[skeletal muscle]]s, [[pancreas]] and [[thyroid]].<ref>{{cite journal |author=Agarwal R, Malhotra P, Awasthi A, Kakkar N, Gupta D |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15857515 |title=Tuberculous dilated cardiomyopathy: an under-recognized entity? |journal=BMC Infect Dis |volume=5 |issue=1 |pages=29 |year=2005 |pmid=15857515}}</ref>
*In young children, the onset of [[Immunity (medical)|immune]] response may be delayed after the [[Bacteria|bacterial]] dissemination  resulting in '''military tuberculosis'''.  Bacteria can spread directly from the primary focus, or from the ''[[Weigart]] focus'' ([[Metastasis|metastatic]] focus adjacent to a [[pulmonary vein]]) through the blood.<ref name="Mandell"></ref><ref name="Kim_2003">{{cite journal |author=Kim J, Park Y, Kim Y, Kang S, Shin J, Park I, Choi B |title=Miliary tuberculosis and acute respiratory distress syndrome |journal=Int J Tuberc Lung Dis |volume=7 |issue=4 |pages=359-64 |year=2003 | pmid = 12733492}}</ref>


TB is a [[granulomatous]] [[inflammatory]] disease.  The granuloma may contain the following cells:<ref name=Kaufmann_2002>{{cite journal |author=Kaufmann S |title=Protection against tuberculosis: cytokines, T cells, and macrophages |journal=Ann Rheum Dis |volume=61 Suppl 2 |issue= |pages=ii54-8 |year=2002 | pmid = 12379623}}</ref>
*In younger patients,  [[rupture]] of [[subpleural]] foci into the [[pleural space]] may occur leading to [[serofibrinous]] [[pleurisy]].<ref name="Mandell"></ref> The most serious site of the M. [[tuberculosis]] dissemination is the postero-apical regions of the lung where it can [[replicate]] hidden from the [[immune system]].<ref name="Mandell"></ref>


* [[Macrophage]]s
==Immunopathogenesis==
* [[T cell|T lymphocytes]]
There are two types of [[Immunity (medical)|immune]] response against [[tuberculosis]] that include the [[Innate immune system|innate]] and [[acquired]] [[Immunity (medical)|immune]] responses. However, the [[Cell-mediated immunity|cell-mediated]] [[Immunity (medical)|immune]] response predominates over the [[Humoral immunity|humoral]] type.
* [[B cell|B lymphocytes]]
===Innate Immune Response===
* [[Fibroblast]]s
Initially, The [[Immunity (medical)|immune]] response generated against ''[[M. tuberculosis]]'' is minimal, enabling it to replicate inside the alveolar [[macrophages]] forming the [[Ghon focus]], or metastatic foci.  Recognition and [[phagocytosis]] of the ''M. tuberculosis'' bacilli by the [[Alveolus|alveolar]] [[Macrophage|macrophages]] occurs through interaction with certain [[Receptor (biochemistry)|receptors]] that are located on the surface of macrophages:<ref name="pmid10358769">{{cite journal| author=Aderem A, Underhill DM| title=Mechanisms of phagocytosis in macrophages. | journal=Annu Rev Immunol | year= 1999 | volume= 17 | issue=  | pages= 593-623 | pmid=10358769 | doi=10.1146/annurev.immunol.17.1.593 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10358769  }} </ref>


The [[granuloma]] prevents the dissemination of [[M. tuberculosis|mycobacteria]] and provides a pathway for [[immune cell]] communication.  Within the [[granuloma]], [[CD4|T lymphocytes]] (CD4) secrete [[cytokines]], such as [[interferon gamma]], which activate local [[macrophages]] to kill the bacteria with which they are infected.<ref name=Kaufmann_2002>{{cite journal |author=Kaufmann S |title=Protection against tuberculosis: cytokines, T cells, and macrophages |journal=Ann Rheum Dis |volume=61 Suppl 2 |issue= |pages=ii54-8 |year=2002 | pmid = 12379623}}</ref>
*[[Toll-like Receptor]] 2 ([[TLR2]])
*[[TLR4]]
*[[TLR9]]
*[[Dectin|Dectin-1]]
*[[DC-SIGN]]
*[[Mannose-binding protein|Mannose]] receptor
*[[Complement]] receptors
*[[NOD2]]


===Primary Infection===
===Acquired Immunity and Granuloma Formation===
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.<ref name="Mandell"></ref>


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'''.<ref name="Mandell"></ref><ref name=Grosset>{{cite journal |author=Grosset J |title=Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary |journal=Antimicrob Agents Chemother |volume=47 |issue=3 |pages=833-6 |year=2003 | pmid = 12604509}}</ref>
*The [[granuloma]] control the [[infection]]; however, it enables the [[mycobacterium]] to survive inside for a long time.


===Progression of the Primary Infection===
*It is important to maintain a balance between the [[pro-inflammatory]] and anti-inflammatory [[Cytokine|cytokines]] released to decrease or control the [[Mycobacterium|mycobacterial]] proliferation.
Initial foci of [[infection]] may evolve into large [[pulmonary]] [[lymph nodes]].  These may lead to:<ref name="Mandell"></ref>
* [[Bronchial]] collapse
* Formation of [[atelectasis]]
* Erosion of the [[bronchus]], with further spread of infection


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.<ref name="Mandell"></ref><ref name="pmid3990748">{{cite journal| author=Stead WW, Lofgren JP, Warren E, Thomas C| title=Tuberculosis as an endemic and nosocomial infection among the elderly in nursing homes. | journal=N Engl J Med | year= 1985 | volume= 312 | issue= 23 | pages= 1483-7 | pmid=3990748 | doi=10.1056/NEJM198506063122304 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3990748  }} </ref><ref name="pmid2274719">{{cite journal| author=Murray JF| title=Cursed duet: HIV infection and tuberculosis. | journal=Respiration | year= 1990 | volume= 57 | issue= 3 | pages= 210-20 | pmid=2274719 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2274719  }} </ref>
*[[Tumor necrosis factor-alpha|TNF-α]] and [[IFN-γ]] stimulate [[granuloma]] formation. On the other hand, [[Interleukin 10|IL-10]] is one of the major negative [[regulators]] and inhibitors of [[granuloma]] formation.


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.<ref name="Mandell"></ref><ref name=Kim_2003>{{cite journal |author=Kim J, Park Y, Kim Y, Kang S, Shin J, Park I, Choi B |title=Miliary tuberculosis and acute respiratory distress syndrome |journal=Int J Tuberc Lung Dis |volume=7 |issue=4 |pages=359-64 |year=2003 | pmid = 12733492}}</ref>
*The [[granuloma]] is structured by blood-derived [[Macrophage|macrophages]] (derived from [[Monocyte|monocytes]]), [[epithelioid]] cells (differentiated [[Macrophage|macrophages]]), and [[multinucleated giant cells]] (also known as [[Langhans giant cell|Langhans giant cells]]), surrounded by [[T lymphocytes]].


In younger patients, serofibrinous [[pleurisy]] is more prone to occur following the rupture of subpleural foci of infection into the [[pleural space]].<ref name="Mandell"></ref>
*[[Caseous granulomas|Caseous granulomas]] are the main characteristic of [[tuberculosis]]. The caseous granulomas include [[epithelioid]] [[Macrophage|macrophages]] and some [[Lymphocyte|lymphocytes]] with a necrotic center.  Other types of [[granuloma]] include non-necrotizing granulomas, that are mainly formed of [[Macrophage|macrophages]] and a few [[Lymphocyte|lymphocytes]], necrotic neutrophilic granulomas, and completely fibrotic granulomas.<ref name="pmid22811737">{{cite journal| author=Silva Miranda M, Breiman A, Allain S, Deknuydt F, Altare F| title=The tuberculous granuloma: an unsuccessful host defense mechanism providing a safe shelter for the bacteria? | journal=Clin Dev Immunol | year= 2012 | volume= 2012 | issue=  | pages= 139127 | pmid=22811737 | doi=10.1155/2012/139127 | pmc=PMC3395138 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22811737  }} </ref>


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.<ref name="Mandell"></ref>
*Several [[Chemokine|chemokines]] are involved in [[granuloma]] formation released either from the [[Respiratory system|respiratory]] tract [[epithelium]] or the [[Immunity (medical)|immune]] cells themselves.


===Age Influence on Tuberculosis===
*Interaction with [[CCR2]] receptor  with ([[CCL2]]/[[MCP-1]], [[CCL12]], and [[CCL13]]) is necessary for the initial [[Recruitment status|recruitment]] of [[Macrophage|macrophages]].
Depending on the age of the patient, tuberculosis may have different clinical manifestations, progression, and prognosis:<ref name="Mandell"></ref><ref name="pmid3990748">{{cite journal| author=Stead WW, Lofgren JP, Warren E, Thomas C| title=Tuberculosis as an endemic and nosocomial infection among the elderly in nursing homes. | journal=N Engl J Med | year= 1985 | volume= 312 | issue= 23 | pages= 1483-7 | pmid=3990748 | doi=10.1056/NEJM198506063122304 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3990748  }} </ref><ref name="pmid13007533">{{cite journal| author=DAHL RH| title=[The first appearance of a pulmonary cavity after primary infection with relation to time and age]. | journal=Acta Tuberc Scand | year= 1952 | volume= 27 | issue= 1-2 | pages= 140-9 | pmid=13007533 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13007533  }} </ref><ref name="pmid4960690">{{cite journal| author=Stead WW| title=Pathogenesis of a first episode of chronic pulmonary tuberculosis in man: recrudescence of residuals of the primary infection or exogenous reinfection? | journal=Am Rev Respir Dis | year= 1967 | volume= 95 | issue= 5 | pages= 729-45 | pmid=4960690 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4960690  }} </ref><ref name="pmid10764341">{{cite journal| author=| title=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. | journal=Am J Respir Crit Care Med | year= 2000 | volume= 161 | issue= 4 Pt 2 | pages= S221-47 | pmid=10764341 | doi=10.1164/ajrccm.161.supplement_3.ats600 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10764341  }} </ref><ref name="pmid13007533">{{cite journal| author=DAHL RH| title=[The first appearance of a pulmonary cavity after primary infection with relation to time and age]. | journal=Acta Tuberc Scand | year= 1952 | volume= 27 | issue= 1-2 | pages= 140-9 | pmid=13007533 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13007533  }} </ref><ref name="pmid5642961">{{cite journal| author=Stead WW, Kerby GR, Schlueter DP, Jordahl CW| title=The clinical spectrum of primary tuberculosis in adults. Confusion with reinfection in the pathogenesis of chronic tuberculosis. | journal=Ann Intern Med | year= 1968 | volume= 68 | issue= 4 | pages= 731-45 | pmid=5642961 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5642961  }} </ref>


{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
*[[Macrophage|Macrophages]] and [[Lymphocyte|lymphocytes]] release a [[chemokine]] called [[osteopontin]] that enhances the [[adhesion]] and [[Recruitment status|recruitment]] of the [[Immunity (medical)|immune]] cells.
|valign=top|
|+
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Factor}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Influence}}
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" | Location
| style="padding: 5px 5px; background: #F5F5F5;" |
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
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" | Infants and Children
| style="padding: 5px 5px; background: #F5F5F5;" |
* 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:
:* [[Lymph nodes]]
:* [[Bones]]
:* Extrapulmonary foci
* Good prognosis, even in the absence of treatment, often with spontaneous healing.
* Cavitary tuberculosis has an higher risk of relapse.
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" | Adolescents
| style="padding: 5px 5px; background: #F5F5F5;" |
* 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.
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" | Midadulthood
| style="padding: 5px 5px; background: #F5F5F5;" |
* If infection is acquired during mid adulthood, the disease has a better prognosis, possibly due to the existence of less [[necrotic]] tissue.
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" | Elderly
| style="padding: 5px 5px; background: #F5F5F5;" |
* 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==
*[[CCL19]] and [[CCL21]] are important for [[Recruitment status|recruitment]] of [[Interferon|IFN]]--producing [[T cell|T cells]].
The immune response against [[M. tuberculosis]] has a great involvement from [[cellular immunity]].<ref name="pmid8501346">{{cite journal| author=Orme IM, Andersen P, Boom WH| title=T cell response to Mycobacterium tuberculosis. | journal=J Infect Dis | year= 1993 | volume= 167 | issue= 6 | pages= 1481-97 | pmid=8501346 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8501346  }} </ref>  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:<ref name="pmid10358769">{{cite journal| author=Aderem A, Underhill DM| title=Mechanisms of phagocytosis in macrophages. | journal=Annu Rev Immunol | year= 1999 | volume= 17 | issue=  | pages= 593-623 | pmid=10358769 | doi=10.1146/annurev.immunol.17.1.593 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10358769  }} </ref>
* [[Fc receptors]]
* [[Mannose]] receptors
* [[Complement]] receptors


Once within [[alveolar]] [[macrophages]], ''[[M. tuberculosis]]'' uses multiple mechanisms in order to survive:<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>
*In [[Tumor necrosis factors|TNF]]-deficient mice, absence of these [[Chemokine|chemokines]] as a result of [[inhibition]] of the [[Gene expression|expression]] of the CC and CXC [[Chemokine|chemokines]] prevents the [[Recruitment status|recruitment]] of other [[Macrophage|macrophages]] and [[T lymphocytes]]. This finding sheds the light on the role of [[Tumor necrosis factors|TNF]] in [[granuloma]] formation.<ref name="pmid22811737">{{cite journal| author=Silva Miranda M, Breiman A, Allain S, Deknuydt F, Altare F| title=The tuberculous granuloma: an unsuccessful host defense mechanism providing a safe shelter for the bacteria? | journal=Clin Dev Immunol | year= 2012 | volume= 2012 | issue=  | pages= 139127 | pmid=22811737 | doi=10.1155/2012/139127 | pmc=PMC3395138 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22811737  }} </ref>
* [[Urease]] - prevents acidification of macrophageal [[lysosomes]], limiting action of cellular [[enzymes]]
* Secretion of [[antioxidant]]s, for suppression of [[reactive oxygen species]], such as:
:* [[Catalase]]
:* [[Superoxide dismutase]]
:* [[Thioredoxin]]
* 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 cell]]s that will be responsible for the formation of the [[granuloma]].<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>
[[File:Granuloma_Formation_in_Tuberculosis.jpg|thumb|center|800px|Following inhalation of contaminated aerosols, M. Tuberculosis moves to the lower respiratory tract where it is recognized by alveolar macrophages. This recognition is mediated by a set of surface receptors (see text), which drive the uptake of the bacteria and trigger innate immune signaling pathways leading to the production of various chemokines and cytokines (a). Epithelial cells and neutrophils can also produce chemokines in response to bacterial products (not represented). This promotes the recruitment of other immune cells (more macrophages, dendritic cells, and lymphocytes) to the infection site (b). They organize in a spherical structure with infected macrophages in the middle surrounded by various categories of lymphocytes (mainly CD4+, CD8+, and γ/δ T cells). Macrophages (MP) can fuse to form MGCs or differentiate into lipid-rich foamy cells (FM). B lymphocytes tend to aggregate in follicular-type structures adjacent to the granuloma ((c), see text for details). The bacteria can survive for decades inside the granuloma in a latent state. Due to some environmental (e.g., HIV infection, malnutrition, etc.) or genetic factors, the bacteria will reactivate and provoke the death of the infected macrophages. A necrotic zone (called caseum due to its milky appearance) will develop in the center of the granuloma (d). Ultimately the structure will disintegrate allowing the exit of the bacteria, which will spread in other parts of the lungs, and more lesions will be formed. The infection will also be transmitted to other individuals due to the release of the infected droplets by coughing (e).<ref name="pmid22811737">{{cite journal| author=Silva Miranda M, Breiman A, Allain S, Deknuydt F, Altare F| title=The tuberculous granuloma: an unsuccessful host defense mechanism providing a safe shelter for the bacteria? | journal=Clin Dev Immunol | year= 2012 | volume= 2012 | issue=  | pages= 139127 | pmid=22811737 | doi=10.1155/2012/139127 | pmc=PMC3395138 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22811737  }} </ref>]]


About 3-9 weeks after the 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 TB.<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>
===Molecular Pathogenesis===


A [[granuloma]] is formed in the presence of a low antigen load, with an hypersensitive tissue response, that is manifested by a large accumulation of host cells, such as:<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>
*The [[mycobacterial]] [[antigens]] are presented on thee surfaces of alveolar [[macrophages]] and [[dendritic cells]] through class II [[major histocompatibility complex]].  These [[antigens]] are recognized by [[CD4]] lymphocytes through αβ [[T cell|T-cell]] receptors. Following that, [[CD4+ cell|CD4]] [[Lymphocyte|lymphocytes]] release [[Chemokine|chemokines]] that recruit more [[macrophages]] to the foci of infection.
* [[Capillaries]]
*[[Interferon gamma (IFN-γ)]] and [[tumor necrosis factor alpha]] ([[Tumor necrosis factor-alpha|TNF-α]]) signaling activates additional [[Macrophage|macrophages]]. <ref name="Tuberculosis">{{cite web | title = Tumor Necrosis Factor alpha| url =http://erj.ersjournals.com/content/36/5/1185.long }}</ref>
* [[Fibroblasts]]
*[[Metalloproteinase]] converts the transmembrane protein to soluble [[Tumor necrosis factor-alpha|TNF-α]] which interacts with the TNFR1 and TNFR2 receptors inducing [[apoptosis]] through [[caspase]]-dependent pathways
* [[Macrophages]]
*TNF along side the [[Synergy|synergistic]] action of [[Interferon-gamma|interferon]]-gamma enhances the [[Phagocytosis|phagocytic]] activity of the [[Macrophage|macrophages]] and facilitates  the intracellular killing of mycobacteria by [[reactive nitrogen and oxygen]] intermediates.
* [[Lymphocytes]]
*[[Neutralization]] of the TNF-α activity leads to the [[Mycobacterium|mycobacteria]] survival within the [[granuloma]] in latent infection.
* [[Langhans giant cells]]
*[[Tumor necrosis factors|TNF]] activates release of [[CCL2]], [[CCL3]], [[CCL4]], [[CCL5]], [[CCL8]] chemokines and increases [[CD54]] leading to accumulation of [[Immunity (medical)|immune]] cells and it is the main element in the process of [[granuloma]] formation and maintenance. <ref name="Tuberculosis">{{cite web | title = Tumor Necrosis Factor and Tuberculosis| url =http://www.nature.com/jidsp/journal/v12/n1/full/5650027a.htm }}</ref>
*The [[immune cells]] release large amounts of lytic enzymes leading to tissue [[necrosis]].


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.<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>


When the reaction of the [[immune system]] is successful, the healing process leads to the formation of a scar on the fibrotic and encapsulated tissue (exudative reaction).  If [[necrosis]] is incomplete, a caseous material may be formed.<ref name="pmid5321145">{{cite journal| author=Canetti G| title=Present aspects of bacterial resistance in tuberculosis. | journal=Am Rev Respir Dis | year= 1965 | volume= 92 | issue= 5 | pages= 687-703 | pmid=5321145 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5321145  }} </ref>
[[File:TNF alpha.png|thumb|center|500px| <SMALL><SMALL> ''[(<nowiki>http://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha#mediaviewer/File:TNF_signaling.jpg</nowiki><nowiki>)]</nowiki>''<ref name="TNF Alpha">{{Cite web | title = TNF Alpha |http://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha#mediaviewer/File:TNF_signaling.jpg url = }}</ref></SMALL></SMALL>]]


If the caseous material is discharged through the [[bronchial]] airways, tuberculous cavities may be formed and coinfected by multiple organisms.  In the absence of necrosis, full healing may occur.<ref name="pmid5321145">{{cite journal| author=Canetti G| title=Present aspects of bacterial resistance in tuberculosis. | journal=Am Rev Respir Dis | year= 1965 | volume= 92 | issue= 5 | pages= 687-703 | pmid=5321145 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5321145  }} </ref>
Once within [[alveolar]] [[macrophages]], ''[[M. tuberculosis]]'' uses multiple mechanisms in order to survive:<ref name="Mandell"></ref>


If the [[immune response]] is weak, nonreactive TB may be noted. In this case, unspecific tissue changes may be noted, with few [[immune cells]] surrounding large amounts of [[bacilli]].<ref name="pmid13192197">{{cite journal| author=O'BRIEN JR| title=Non-reactive tuberculosis. | journal=J Clin Pathol | year= 1954 | volume= 7 | issue= 3 | pages= 216-25 | pmid=13192197 | doi= | pmc=PMC1023795 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13192197  }} </ref>
*[[Urease]] - prevents acidification of macrophageal [[lysosomes]], limiting action of cellular [[enzymes]]
*Secretion of [[antioxidant]]s, for suppression of [[reactive oxygen species]], such as:


In persons with a positive [[TST]], endogenous foci of bacteria may be reactivated.  [[CD4]] lymphocytes are responsible for inhibiting this reactivation.<ref name="pmid9359738">{{cite journal| author=Ellner JJ| title=Review: the immune response in human tuberculosis--implications for tuberculosis control. | journal=J Infect Dis | year= 1997 | volume= 176 | issue= 5 | pages= 1351-9 | pmid=9359738 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9359738  }} </ref>
:*[[Catalase]]
:*[[Superoxide dismutase]]
:*[[Thioredoxin]]


==Transmission==
==Transmission==
After contact with a patient that has the active form of the disease, and inhalation of the ''[[M. tuberculosis]]'' the risk of developing active tuberculosis is low, with a life-time projected risk of about 10%.<ref name="pmid23460002">{{cite journal| author=Glaziou P, Falzon D, Floyd K, Raviglione M| title=Global epidemiology of tuberculosis. | journal=Semin Respir Crit Care Med | year= 2013 | volume= 34 | issue= 1 | pages= 3-16 | pmid=23460002 | doi=10.1055/s-0032-1333467 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23460002  }} </ref>  The probability of [[transmission]] from one person to another depends on the number of [[infectious]] droplets expelled by the carrier, the effectiveness of ventilation, the duration of the exposure, and the [[virulence]] of the strain of ''M. tuberculosis''.<ref>{{cite web|url=http://www.mayoclinic.com/health/tuberculosis/DS00372/DSECTION=3|title=Causes of Tuberculosis|accessdate=2007-10-19|date=2006-12-21|last=|first=|publisher=[[Mayo Clinic]]}}</ref>  The probability of transmitting the disease is highest during the first years, after the person has been infected, decreasing thenceforth.<ref name="pmid21420161">{{cite journal| author=Lawn SD, Zumla AI| title=Tuberculosis. | journal=Lancet | year= 2011 | volume= 378 | issue= 9785 | pages= 57-72 | pmid=21420161 | doi=10.1016/S0140-6736(10)62173-3 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21420161  }} </ref>
After contact with a patient having the active [[Tuberculosis|TB]], and [[inhalation]] of the ''[[M. tuberculosis]],'' the risk of developing active [[tuberculosis]] is low with a life-time risk of about 10%.<ref name="pmid23460002">{{cite journal| author=Glaziou P, Falzon D, Floyd K, Raviglione M| title=Global epidemiology of tuberculosis. | journal=Semin Respir Crit Care Med | year= 2013 | volume= 34 | issue= 1 | pages= 3-16 | pmid=23460002 | doi=10.1055/s-0032-1333467 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23460002  }} </ref>  The probability of [[transmission]] between individuals depends on the number of expelled [[infectious]] droplets the ventilation, the duration of the [[Exposure effect|exposure]], [[Immunity (medical)|immunity]], and the [[virulence]] of the ''[[Mycobacterium tuberculosis|M. tuberculosis]] strain''.<ref>{{cite web|url=http://www.mayoclinic.com/health/tuberculosis/DS00372/DSECTION=3|title=Causes of Tuberculosis|accessdate=2007-10-19|date=2006-12-21|last=|first=|publisher=[[Mayo Clinic]]}}</ref>  The [[probability]] of transmitting the [[infection]] is highest during the first years of getting the infection. After that, it decreases.<ref name="pmid21420161">{{cite journal| author=Lawn SD, Zumla AI| title=Tuberculosis. | journal=Lancet | year= 2011 | volume= 378 | issue= 9785 | pages= 57-72 | pmid=21420161 | doi=10.1016/S0140-6736(10)62173-3 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21420161  }} </ref>


In rare occasions, the bacteria may be transmitted through other routes, besides the [[pulmonary]]. In these cases, the formation of foci in local [[lymph nodes]] is always involved.  These alternative routes of [[transmission]] include:<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>
In rare occasions, the [[Mycobacterium|mycobacteria]] can be [[transmitted]] by other ways apart from the [[Respiratory system|respiratory]] route in which, the formation of foci in the regional [[lymph nodes]] frequently occurs.  Those routes include:<ref name="Mandell"></ref>
* [[Skin]] abrasions
 
* [[Oropharynx]]
*[[Skin]] [[Abrasion|abrasions]]
* [[Intestine]]
*[[Oropharynx]]
* [[Genitalia]]
*[[Intestine]]
*[[Genitalia]]


==Associated Conditions==
==Associated Conditions==
===AIDS===
===AIDS===
Tuberculosis influences the progression of [[HIV]] [[viral replication|replication]] in infected patients, leading to an increase in the [[mortality rate]].<ref name="pmid23425167">{{cite journal| author=Zumla A, Raviglione M, Hafner R, von Reyn CF| title=Tuberculosis. | journal=N Engl J Med | year= 2013 | volume= 368 | issue= 8 | pages= 745-55 | pmid=23425167 | doi=10.1056/NEJMra1200894 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23425167  }} </ref>


On the other hand, [[HIV]] infected patients, particularly those with low counts of [[CD4|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 disease.<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref><ref name="pmid1345800">{{cite journal| author=Daley CL, Small PM, Schecter GF, Schoolnik GK, McAdam RA, Jacobs WR et al.| title=An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragment-length polymorphisms. | journal=N Engl J Med | year= 1992 | volume= 326 | issue= 4 | pages= 231-5 | pmid=1345800 | doi=10.1056/NEJM199201233260404 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1345800  }} </ref><ref name="pmid8280411">{{cite journal| author=Bouvet E, Casalino E, Mendoza-Sassi G, Lariven S, Vallée E, Pernet M et al.| title=A nosocomial outbreak of multidrug-resistant Mycobacterium bovis among HIV-infected patients. A case-control study. | journal=AIDS | year= 1993 | volume= 7 | issue= 11 | pages= 1453-60 | pmid=8280411 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8280411  }} </ref> It is still not known if [[AIDS]] influences the risk of [[infection]], when in contact with the ''[[M. tuberculosis]]''.<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>
*[[Tuberculosis]] influence the progression of [[HIV]] [[viral replication|replication]] leading to an increase in in the [[mortality rate]].<ref name="pmid23425167">{{cite journal| author=Zumla A, Raviglione M, Hafner R, von Reyn CF| title=Tuberculosis. | journal=N Engl J Med | year= 2013 | volume= 368 | issue= 8 | pages= 745-55 | pmid=23425167 | doi=10.1056/NEJMra1200894 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23425167  }} </ref>
 
*[[HIV]] infected patients, particularly those having low [[CD4|CD4 lymphocytes]] counts, are more likely to develop reactivation of latent [[tuberculosis]].  Moreover, when an individual has been recently infected with ''[[M. tuberculosis]]'', they progress rapidly into active disease.<ref name="Mandell"></ref><ref name="pmid1345800">{{cite journal| author=Daley CL, Small PM, Schecter GF, Schoolnik GK, McAdam RA, Jacobs WR et al.| title=An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragment-length polymorphisms. | journal=N Engl J Med | year= 1992 | volume= 326 | issue= 4 | pages= 231-5 | pmid=1345800 | doi=10.1056/NEJM199201233260404 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1345800  }} </ref><ref name="pmid8280411">{{cite journal| author=Bouvet E, Casalino E, Mendoza-Sassi G, Lariven S, Vallée E, Pernet M et al.| title=A nosocomial outbreak of multidrug-resistant Mycobacterium bovis among HIV-infected patients. A case-control study. | journal=AIDS | year= 1993 | volume= 7 | issue= 11 | pages= 1453-60 | pmid=8280411 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8280411  }} </ref> The correlation between [[AIDS]] and the risk of TB [[infection]] is still not fully understood.<ref name="Mandell"></ref>
 
Patients with [[AIDS]] are more prone to get [[pulmonary]] and [[extrapulmonary tuberculosis]]. [[Extrapulmonary tuberculosis|Extrapulmonary]] disease in [[HIV AIDS|AIDS]] patients has characteristic [[manifestations]], such as:<ref name="Mandell"></ref>
 
*Higher risk of progression into [[Disseminated TB|disseminated]] disease<ref name="pmid1956280">{{cite journal| author=Shafer RW, Kim DS, Weiss JP, Quale JM| title=Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. | journal=Medicine (Baltimore) | year= 1991 | volume= 70 | issue= 6 | pages= 384-97 | pmid=1956280 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1956280  }} </ref>
*[[DIC]] and acute [[respiratory failure]]
*[[Tuberculosis|Tuberculous]] [[pleuritis]] occurs bilaterally
*[[Abdominal]] and [[Mediastinum|mediastinal]] [[lymphadenopathy]] frequently occurs
*Higher risk of [[Immune reconstitution inflammatory syndrome]] ([[IRIS]])<ref name="pmid18652998">{{cite journal| author=Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W et al.| title=Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. | journal=Lancet Infect Dis | year= 2008 | volume= 8 | issue= 8 | pages= 516-23 | pmid=18652998 | doi=10.1016/S1473-3099(08)70184-1 | pmc=PMC2804035 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18652998  }} </ref>
*Common [[abscesses]] of:<ref name="Mandell"></ref>


Patients with [[AIDS]] have increased risk of developing [[pulmonary]] and [[extrapulmonary tuberculosis]].  Extrapulmonary disease in this group of patients has characteristic manifestations, such as:<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>
* Higher frequency of disseminated disease<ref name="pmid1956280">{{cite journal| author=Shafer RW, Kim DS, Weiss JP, Quale JM| title=Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. | journal=Medicine (Baltimore) | year= 1991 | volume= 70 | issue= 6 | pages= 384-97 | pmid=1956280 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1956280  }} </ref>
* Rapid progression of the disease with widespread [[pulmonary]] infiltrates
* [[DIC]] and acute [[respiratory failure]]
* When present, tuberculous [[pleuritis]] occurs bilaterally
* Abdominal and mediastinal [[lymphadenopathy]] are common
* Increased risk of [[Immune reconstitution inflammatory syndrome]] ([[IRIS]])<ref name="pmid18652998">{{cite journal| author=Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W et al.| title=Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. | journal=Lancet Infect Dis | year= 2008 | volume= 8 | issue= 8 | pages= 516-23 | pmid=18652998 | doi=10.1016/S1473-3099(08)70184-1 | pmc=PMC2804035 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18652998  }} </ref>
* Common [[abscesses]] of:<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>
:*[[Pancreas]]
:*[[Pancreas]]
:*[[Liver]]
:*[[Liver]]
Line 162: Line 136:
==Gallery==
==Gallery==
<gallery>
<gallery>
 
File:TB1.jpg|Left lateral margin of a tongue of a tuberculosis patient, which had been retracted in order to reveal the lesion that had been caused by the Gram-positive bacterium Mycobacterium tuberculosis<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:TB1.jpg|Left lateral margin of a tongue of a tuberculosis patient, which had been retracted in order to reveal the lesion that had been caused by the Gram-positive bacterium Mycobacterium tuberculosis<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
File:TB2.jpg|<SMALL><SMALL>''Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection.[ http://phil.cdc.gov/phil/<nowiki> Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]</nowiki>''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
File:Leprosy-35.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:TB2.jpg|<SMALL><SMALL>''Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection.[ http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
File:Leprosy-36.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
File:Leprosy-37.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:Leprosy-35.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
File:Leprosy-38.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
File:TB3.jpg| Photomicrograph describing tuberculosis of the placenta.<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:Leprosy-36.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
File:TB4.jpg| Histopathology of tuberculosis, endometrium. Ziehl-Neelsen stain.<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
File:TB5.jpg| Histopathology of tuberculosis, placenta.<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:Leprosy-37.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
File:Miliar TB.JPG|Miliar Tuberculosis
 
File:Renal TB.jpg|Renal Tuberculosis lesion
Image:Leprosy-38.jpg| Light photomicrograph revealing some of the histopathologic cytoarchitectural characteristics seen in a mycobacterial skin infection <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:TB3.jpg| Photomicrograph describing tuberculosis of the placenta.<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:TB4.jpg| Histopathology of tuberculosis, endometrium. Ziehl-Neelsen stain.<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:TB5.jpg| Histopathology of tuberculosis, placenta.<SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:Miliar TB.JPG|Miliar Tuberculosis
 
Image:Renal TB.jpg|Renal Tuberculosis lesion
</gallery>
</gallery>


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[[Category:Primary care]]

Latest revision as of 05:09, 28 February 2021

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Tuberculosis Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mashal Awais, M.D.[2], João André Alves Silva, M.D. [3]

Overview

Transmission of M. tuberculosis occurs when individuals with active pulmonary disease cough, speak, sneeze or sing expelling the infectious droplets. The mycobacterium tuberculosis favors the upper lung lobes due to the high oxygen level. Tuberculosis is a prototypical granulomatous infection. The granuloma surrounds the mycobacteria and prevents their dissemination and facilitates the immune cell interaction. Within the granuloma, CD4 T lymphocytes release chemokines that activate local macrophages and recruit other immune cells..

Pathogenesis

Transmission of M. tuberculosis occurs when individuals with active pulmonary disease cough, speak, sneeze or sing expelling the infectious droplets that can pass to the terminal bronchioles and alveoli then phagocytosed by alveolar macrophages where they can replicate in the endosomes of alveolar macrophages. As a part of the immune response by these macrophages, the alveolar macrophages release cytokines that recruits further macrophages, neutrophils, and monocytes, surrounding the bacilli. Despite having a very low infectious dose (ID<200 bacteria), 90% of the infected immunocompetent individuals are asymptomatic. In most cases, the bacteria may either be eliminated or enclosed within a granuloma. The granuloma is a structured, radial aggregation of macrophages, epithelioid cells, T lymphocytes, B lymphocytes, and fibroblasts that prevents the spreading of mycobacteria and enhances interaction of the immune cells.[1] The primary site of infection in the lung is called the Ghon focus that is mainly located in either the upper part of the lower lobe, or the lower part of the upper lobe.[1][2]

Primary Infection

The infected macrophages are transported through the lymphatics to the regional lymph nodes in the immunocompetent individuals. However, with impaired immune response, these macrophages can pass through the bloodstream to enter any part of the body. Those foci of primary infection usually resolve without any consequences, but they can act as a foci of M. tuberculosis dissemination. There are particular organs that are more susceptible to bacterial replication as well as being potential metastatic foci which include:[1][2]

Although TB is a systemic disease and all organs can be affected, the heart, pancreas, skeletal muscles and thyroid are rarely involved.[3] In a few cases, when the infectious dose is high and antigens concentration in the primary focus is high, the immune response and hypersensitivity can lead to necrosis and calcification of this lesion, and these primary calcified foci are then called Ranke complex.[1][4]

Progression of the Primary Infection

Primary foci of infection can enter the large pulmonary lymph nodes. These may lead to:[1]

  • In non-caucasian children, elderly patients and HIV/AIDS, the immune response is impaired, consequently the primary focus of infection can deteriorate into progressive primary disease, with advancing pneumonia.
  • In young children, the onset of immune response may be delayed after the bacterial dissemination resulting in military tuberculosis. Bacteria can spread directly from the primary focus, or from the Weigart focus (metastatic focus adjacent to a pulmonary vein) through the blood.[1][7]

Immunopathogenesis

There are two types of immune response against tuberculosis that include the innate and acquired immune responses. However, the cell-mediated immune response predominates over the humoral type.

Innate Immune Response

Initially, The immune response generated against M. tuberculosis is minimal, enabling it to replicate inside the alveolar macrophages forming the Ghon focus, or metastatic foci. Recognition and phagocytosis of the M. tuberculosis bacilli by the alveolar macrophages occurs through interaction with certain receptors that are located on the surface of macrophages:[8]

Acquired Immunity and Granuloma Formation

Following inhalation of contaminated aerosols, M. Tuberculosis moves to the lower respiratory tract where it is recognized by alveolar macrophages. This recognition is mediated by a set of surface receptors (see text), which drive the uptake of the bacteria and trigger innate immune signaling pathways leading to the production of various chemokines and cytokines (a). Epithelial cells and neutrophils can also produce chemokines in response to bacterial products (not represented). This promotes the recruitment of other immune cells (more macrophages, dendritic cells, and lymphocytes) to the infection site (b). They organize in a spherical structure with infected macrophages in the middle surrounded by various categories of lymphocytes (mainly CD4+, CD8+, and γ/δ T cells). Macrophages (MP) can fuse to form MGCs or differentiate into lipid-rich foamy cells (FM). B lymphocytes tend to aggregate in follicular-type structures adjacent to the granuloma ((c), see text for details). The bacteria can survive for decades inside the granuloma in a latent state. Due to some environmental (e.g., HIV infection, malnutrition, etc.) or genetic factors, the bacteria will reactivate and provoke the death of the infected macrophages. A necrotic zone (called caseum due to its milky appearance) will develop in the center of the granuloma (d). Ultimately the structure will disintegrate allowing the exit of the bacteria, which will spread in other parts of the lungs, and more lesions will be formed. The infection will also be transmitted to other individuals due to the release of the infected droplets by coughing (e).[9]

Molecular Pathogenesis


[(http://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha#mediaviewer/File:TNF_signaling.jpg)][11]

Once within alveolar macrophages, M. tuberculosis uses multiple mechanisms in order to survive:[1]

Transmission

After contact with a patient having the active TB, and inhalation of the M. tuberculosis, the risk of developing active tuberculosis is low with a life-time risk of about 10%.[12] The probability of transmission between individuals depends on the number of expelled infectious droplets the ventilation, the duration of the exposure, immunity, and the virulence of the M. tuberculosis strain.[13] The probability of transmitting the infection is highest during the first years of getting the infection. After that, it decreases.[14]

In rare occasions, the mycobacteria can be transmitted by other ways apart from the respiratory route in which, the formation of foci in the regional lymph nodes frequently occurs. Those routes include:[1]

Associated Conditions

AIDS

  • HIV infected patients, particularly those having low CD4 lymphocytes counts, are more likely to develop reactivation of latent tuberculosis. Moreover, when an individual has been recently infected with M. tuberculosis, they progress rapidly into active disease.[1][16][17] The correlation between AIDS and the risk of TB infection is still not fully understood.[1]

Patients with AIDS are more prone to get pulmonary and extrapulmonary tuberculosis. Extrapulmonary disease in AIDS patients has characteristic manifestations, such as:[1]

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 1.11 1.12 1.13 1.14 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. ↑ Grosset J (2003). "Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary". Antimicrob Agents Chemother. 47 (3): 833–6. PMID 12604509.
  5. ↑ 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.
  6. ↑ Murray JF (1990). "Cursed duet: HIV infection and tuberculosis". Respiration. 57 (3): 210–20. PMID 2274719.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 9.0 9.1 9.2 Silva Miranda M, Breiman A, Allain S, Deknuydt F, Altare F (2012). "The tuberculous granuloma: an unsuccessful host defense mechanism providing a safe shelter for the bacteria?". Clin Dev Immunol. 2012: 139127. doi:10.1155/2012/139127. PMC 3395138. PMID 22811737.
  10. ↑ 10.0 10.1 "Tumor Necrosis Factor alpha".
  11. ↑ "TNF Alpha". Missing or empty |url= (help)
  12. ↑ 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.
  13. ↑ "Causes of Tuberculosis". Mayo Clinic. 2006-12-21. Retrieved 2007-10-19.
  14. ↑ Lawn SD, Zumla AI (2011). "Tuberculosis". Lancet. 378 (9785): 57–72. doi:10.1016/S0140-6736(10)62173-3. PMID 21420161.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 20.8 "Public Health Image Library (PHIL), Centers for Disease Control and Prevention".

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