Anthrax pathophysiology: Difference between revisions

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:* Edema Factor (EF)
:* Edema Factor (EF)


* pXO2 - encodes proteins involved in the [[glutamic acid]] [[capsule]] structure, which is responsible for conferring [[resistance]] against [[phagocytosis]]
* pXO2 - encodes proteins involved in the [[glutamic acid]] [[capsule]] structure which is responsible for conferring [[resistance]] against [[phagocytosis]].


==Transmission==
==Transmission==
The route by which anthrax is transmitted allows for its classification. It includes:<ref name=WHO>{{cite web | title = Anthrax in Humans and Animals | url = http://www.who.int/csr/resources/publications/anthrax_web.pdf }}</ref>
The route of transmission of anthrax allows for its classification into the following:<ref name=WHO>{{cite web | title = Anthrax in Humans and Animals | url = http://www.who.int/csr/resources/publications/anthrax_web.pdf }}</ref>
* Cutaneous anthrax - commonly requires a prior [[skin lesion]] as a prerequisite for [[infection]]
* Cutaneous anthrax - commonly requires a prior [[skin lesion]] as a prerequisite for [[infection]]
* Gastrointestinal anthrax - contracted following [[ingestion]] of contaminated food, primarily meat from an animal that died of the disease, or conceivably from [[ingestion]] of contaminated water
* Gastrointestinal anthrax - contracted following [[ingestion]] of contaminated food, primarily meat from an animal that died of the disease, or conceivably from [[ingestion]] of contaminated water
* Inhalational anthrax - from breathing in airborne anthrax [[spores]]  
* Inhalational anthrax - from breathing in airborne anthrax [[spores]]  
* Injection anthrax - from injection of a [[drug]] containing, or contaminated with [[Bacillus anthracis]]
* Injection anthrax - from the injection of a [[drug]] containing or contaminated with [[Bacillus anthracis]]


==Pathogenesis==
==Pathogenesis==
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[[B. anthracis]] begins to produce [[toxins]] within hours of germination.<ref name="HannaIreland1999">{{cite journal|last1=Hanna|first1=Philip C.|last2=Ireland|first2=John A.W.|title=Understanding Bacillus anthracis pathogenesis|journal=Trends in Microbiology|volume=7|issue=5|year=1999|pages=180–182|issn=0966842X|doi=10.1016/S0966-842X(99)01507-3}}</ref>
[[B. anthracis]] begins to produce [[toxins]] within hours of germination.<ref name="HannaIreland1999">{{cite journal|last1=Hanna|first1=Philip C.|last2=Ireland|first2=John A.W.|title=Understanding Bacillus anthracis pathogenesis|journal=Trends in Microbiology|volume=7|issue=5|year=1999|pages=180–182|issn=0966842X|doi=10.1016/S0966-842X(99)01507-3}}</ref>
Protective antigen (PA) and edema factor (EF) combine to form edema toxin (ET), and PA and lethal factor (LF) combine to form lethal toxin (LT). After binding to surface receptors, the PA portion of the complexes facilitates translocation of the [[toxins]] to the [[cytosol]], in which EF and LF exert their toxic effects.<ref name="Moayeri2004">{{cite journal|last1=Moayeri|first1=M|title=The roles of anthrax toxin in pathogenesis|journal=Current Opinion in Microbiology|volume=7|issue=1|year=2004|pages=19–24|issn=13695274|doi=10.1016/j.mib.2003.12.001}}</ref>
Protective antigen (PA) and edema factor (EF) combine to form edema toxin (ET), and PA and lethal factor (LF) combine to form lethal toxin (LT). After binding to surface receptors, the PA portion of the complexes facilitates translocation of the [[toxins]] to the [[cytosol]], in which EF and LF exert their toxic effects.<ref name="Moayeri2004">{{cite journal|last1=Moayeri|first1=M|title=The roles of anthrax toxin in pathogenesis|journal=Current Opinion in Microbiology|volume=7|issue=1|year=2004|pages=19–24|issn=13695274|doi=10.1016/j.mib.2003.12.001}}</ref>
[[Bacillus anthracis]] disseminate to multiple organs including [[spleen]], [[liver]], [[intestines]], [[kidneys]], [[adrenal glands]], and [[meninges]], affecting their normal functions, leading to systemic [[infection]] and a potentially fatal outcome.<ref>{{cite book | last = Rubin | first = Raphael | title = Rubin's pathology : clinicopathologic foundations of medicine | publisher = Wolters Kluwer Health/Lippincott Williams & Wilkins | location = Philadelphia | year = 2012 | isbn = 1605479683 }}</ref><ref>{{cite book | last = Kumar | first = Vinay | title = Robbins and Cotran pathologic basis of disease | publisher = Elsevier/Saunders | location = Philadelphia, PA | year = 2014 | isbn = 0323266169 }}</ref><ref name=WHO>{{cite web | title = Anthrax in Humans and Animals | url = http://www.who.int/csr/resources/publications/anthrax_web.pdf }}</ref>
[[Bacillus anthracis]] disseminate to multiple organs including [[spleen]], [[liver]], [[intestines]], [[kidneys]], [[adrenal glands]], and [[meninges]], affecting their normal functions and leading to systemic [[infection]] with a potentially fatal outcome.<ref>{{cite book | last = Rubin | first = Raphael | title = Rubin's pathology : clinicopathologic foundations of medicine | publisher = Wolters Kluwer Health/Lippincott Williams & Wilkins | location = Philadelphia | year = 2012 | isbn = 1605479683 }}</ref><ref>{{cite book | last = Kumar | first = Vinay | title = Robbins and Cotran pathologic basis of disease | publisher = Elsevier/Saunders | location = Philadelphia, PA | year = 2014 | isbn = 0323266169 }}</ref><ref name=WHO>{{cite web | title = Anthrax in Humans and Animals | url = http://www.who.int/csr/resources/publications/anthrax_web.pdf }}</ref>


The [[virulence factors]] of [[Bacillus anthracis]] are:
The [[virulence factors]] of [[Bacillus anthracis]] are:
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===Bacterial Toxins===
===Bacterial Toxins===
In order to [[infect]] the body, [[Bacillus anthracis]] must produce [[toxins]]. These have 3 main toxic effects: [[edema]], [[hemorrhage]] and [[necrosis]]. Besides their direct [[toxic]] effects, responsible for tissue damage, [[anthrax]] [[toxins]] are also responsible for interfering with [[cellular]] pathways, in such way that defense functions of the host's [[immune system]] are affected. This will ultimately allow initial systemic [[infection]], by interfering with the [[immune system]].<ref name="LiuMoayeri2014">{{cite journal|last1=Liu|first1=Shihui|last2=Moayeri|first2=Mahtab|last3=Leppla|first3=Stephen H.|title=Anthrax lethal and edema toxins in anthrax pathogenesis|journal=Trends in Microbiology|volume=22|issue=6|year=2014|pages=317–325|issn=0966842X|doi=10.1016/j.tim.2014.02.012}}</ref>
In order to [[infect]] the body, [[Bacillus anthracis]] must produce [[toxins]]. These toxins have 3 main toxic effects: [[edema]], [[hemorrhage]], and [[necrosis]]. Besides their direct [[toxic]] effects responsible for tissue damage, [[anthrax]] [[toxins]] are also responsible for interfering with [[cellular]] pathways, in such way that defense functions of the host's [[immune system]] are affected. This will ultimately allow initial systemic [[infection]] by interfering with the [[immune system]].<ref name="LiuMoayeri2014">{{cite journal|last1=Liu|first1=Shihui|last2=Moayeri|first2=Mahtab|last3=Leppla|first3=Stephen H.|title=Anthrax lethal and edema toxins in anthrax pathogenesis|journal=Trends in Microbiology|volume=22|issue=6|year=2014|pages=317–325|issn=0966842X|doi=10.1016/j.tim.2014.02.012}}</ref>


When isolated, the 3 structural elements of the anthrax [[exotoxins]] are non-toxic. However, when combined, they form [[virulent]] [[exotoxins]]:<ref name="LiuMoayeri2014">{{cite journal|last1=Liu|first1=Shihui|last2=Moayeri|first2=Mahtab|last3=Leppla|first3=Stephen H.|title=Anthrax lethal and edema toxins in anthrax pathogenesis|journal=Trends in Microbiology|volume=22|issue=6|year=2014|pages=317–325|issn=0966842X|doi=10.1016/j.tim.2014.02.012}}</ref>
When isolated, the 3 structural elements of the anthrax [[exotoxins]] are non-toxic. However, when combined, they form [[virulent]] [[exotoxins]]:<ref name="LiuMoayeri2014">{{cite journal|last1=Liu|first1=Shihui|last2=Moayeri|first2=Mahtab|last3=Leppla|first3=Stephen H.|title=Anthrax lethal and edema toxins in anthrax pathogenesis|journal=Trends in Microbiology|volume=22|issue=6|year=2014|pages=317–325|issn=0966842X|doi=10.1016/j.tim.2014.02.012}}</ref>
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The PA is responsible for attaching the [[toxin]] to the [[cell]], while the LF and the EF are responsible for the [[toxicity]].<ref name="LiuMoayeri2014">{{cite journal|last1=Liu|first1=Shihui|last2=Moayeri|first2=Mahtab|last3=Leppla|first3=Stephen H.|title=Anthrax lethal and edema toxins in anthrax pathogenesis|journal=Trends in Microbiology|volume=22|issue=6|year=2014|pages=317–325|issn=0966842X|doi=10.1016/j.tim.2014.02.012}}</ref>
The PA is responsible for attaching the [[toxin]] to the [[cell]], while the LF and the EF are responsible for the [[toxicity]].<ref name="LiuMoayeri2014">{{cite journal|last1=Liu|first1=Shihui|last2=Moayeri|first2=Mahtab|last3=Leppla|first3=Stephen H.|title=Anthrax lethal and edema toxins in anthrax pathogenesis|journal=Trends in Microbiology|volume=22|issue=6|year=2014|pages=317–325|issn=0966842X|doi=10.1016/j.tim.2014.02.012}}</ref>


After germinating, [[B. anthracis]] produces and releases into the [[blood stream]] PA, LF and EF [[toxins]] separately. However, PA is secreted in its inactivated form (PA). In order to form the [[exotoxin]] complexes with LF and EF, it must first be activated by host-cellular receptors:<ref name="LiuMoayeri2014">{{cite journal|last1=Liu|first1=Shihui|last2=Moayeri|first2=Mahtab|last3=Leppla|first3=Stephen H.|title=Anthrax lethal and edema toxins in anthrax pathogenesis|journal=Trends in Microbiology|volume=22|issue=6|year=2014|pages=317–325|issn=0966842X|doi=10.1016/j.tim.2014.02.012}}</ref>
After germinating, [[B. anthracis]] produces and releases into the [[blood stream]] PA, LF, and EF [[toxins]] separately. However, PA is secreted in its inactivated form (PA). In order to form the [[exotoxin]] complexes with LF and EF, it must first be activated by host-cellular receptors:<ref name="LiuMoayeri2014">{{cite journal|last1=Liu|first1=Shihui|last2=Moayeri|first2=Mahtab|last3=Leppla|first3=Stephen H.|title=Anthrax lethal and edema toxins in anthrax pathogenesis|journal=Trends in Microbiology|volume=22|issue=6|year=2014|pages=317–325|issn=0966842X|doi=10.1016/j.tim.2014.02.012}}</ref>
* CMG2 - ''Capillary Morphogenesis Protein 2'' (predominant toxin receptor''in vivo'')
* CMG2 - ''Capillary Morphogenesis Protein 2'' (predominant toxin receptor''in vivo'')
* TEM8 - ''Tumor Endothelium Marker 8'' (minor role)
* TEM8 - ''Tumor Endothelium Marker 8'' (minor role)
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The acidic environment within the [[endosomes]] leads to the formation of a channel called ''PA63 oligomer channel'', on the endosomal membrane. LF and EF are then released in the [[cytosol]] of the host [[cell]], to then exert their [[toxic]] effects.<ref name="LiuMoayeri2014">{{cite journal|last1=Liu|first1=Shihui|last2=Moayeri|first2=Mahtab|last3=Leppla|first3=Stephen H.|title=Anthrax lethal and edema toxins in anthrax pathogenesis|journal=Trends in Microbiology|volume=22|issue=6|year=2014|pages=317–325|issn=0966842X|doi=10.1016/j.tim.2014.02.012}}</ref>
The acidic environment within the [[endosomes]] leads to the formation of a channel called ''PA63 oligomer channel'', on the endosomal membrane. LF and EF are then released in the [[cytosol]] of the host [[cell]], to then exert their [[toxic]] effects.<ref name="LiuMoayeri2014">{{cite journal|last1=Liu|first1=Shihui|last2=Moayeri|first2=Mahtab|last3=Leppla|first3=Stephen H.|title=Anthrax lethal and edema toxins in anthrax pathogenesis|journal=Trends in Microbiology|volume=22|issue=6|year=2014|pages=317–325|issn=0966842X|doi=10.1016/j.tim.2014.02.012}}</ref>


After experiments in mice, edema toxin was noted to be the major [[virulence factor]], since it caused death of mice in much lesser dosages than lethal toxin.  
After experiments in mice, edema toxin was noted to be the major [[virulence factor]] since it caused death of mice in much lesser dosages than lethal toxin.  
* Edema toxin is a calmodulin-dependent [[adenylyl cyclase]], known to increase [[intracellular]] [[cAMP]] through the conversion of [[ATP]] into [[cAMP]], thus affecting several [[intracellular]] pathways.  
* Edema toxin is a calmodulin-dependent [[adenylyl cyclase]], known to increase [[intracellular]] [[cAMP]] through the conversion of [[ATP]] into [[cAMP]], thus affecting several [[intracellular]] pathways.  
* Lethal toxin is a zinc-dependent metaloproteinase, known to interfere with the mitogen-activated protein kinase (MEK), thereby hampering multiple [[intracellular]] mechanisms.<ref name="LiuMoayeri2014">{{cite journal|last1=Liu|first1=Shihui|last2=Moayeri|first2=Mahtab|last3=Leppla|first3=Stephen H.|title=Anthrax lethal and edema toxins in anthrax pathogenesis|journal=Trends in Microbiology|volume=22|issue=6|year=2014|pages=317–325|issn=0966842X|doi=10.1016/j.tim.2014.02.012}}</ref>
* Lethal toxin is a zinc-dependent metaloproteinase known to interfere with the mitogen-activated protein kinase (MEK), thereby hampering multiple [[intracellular]] mechanisms.<ref name="LiuMoayeri2014">{{cite journal|last1=Liu|first1=Shihui|last2=Moayeri|first2=Mahtab|last3=Leppla|first3=Stephen H.|title=Anthrax lethal and edema toxins in anthrax pathogenesis|journal=Trends in Microbiology|volume=22|issue=6|year=2014|pages=317–325|issn=0966842X|doi=10.1016/j.tim.2014.02.012}}</ref>


===Cutaneous or Injection Anthrax===
===Cutaneous or Injection Anthrax===
According to animal studies, injected [[spores]] in the [[skin]] of susceptible animals (either through a lesion or by injection), germinated and gave rise, in about 2 - 4 hours, to a small [[edema|edematous]] area containing capsulated [[bacilli]]. The following stages were noticed:<ref name=WHO>{{cite web | title = Anthrax in Humans and Animals | url = http://www.who.int/csr/resources/publications/anthrax_web.pdf }}</ref>
According to animal studies, [[spores]] that enter the [[skin]] of susceptible animals (either through a lesion or by injection) germinate and give rise, in about 2 - 4 hours, to a small [[edema|edematous]] area containing capsulated [[bacilli]]. The following stages are noticed:<ref name=WHO>{{cite web | title = Anthrax in Humans and Animals | url = http://www.who.int/csr/resources/publications/anthrax_web.pdf }}</ref>
* The lesion increases in size and becomes defined by a zone of altered [[capillaries]] through [[dilatation]], [[congestion]] and [[swelling]] of the [[endothelial cells]], and [[diapedesis]] of [[neutrophils]]
* The lesion increases in size and becomes defined by a zone of altered [[capillaries]] through [[dilatation]], [[congestion]], and [[swelling]] of the [[endothelial cells]] and through [[diapedesis]] of [[neutrophils]].
* [[Macrophages]] and [[fibrin]] deposits appear, and the efferent [[lymphatics]] become dilated
* [[Macrophages]] and [[fibrin]] deposits appear, and the efferent [[lymphatics]] become dilated.
* Continued multiplication of the [[bacilli]] in the lesion leads to fragmentation of the [[connective tissue]], as the [[edema]] spreads extensively away from the [[infection]] site
* Continued multiplication of the [[bacilli]] in the lesion leads to fragmentation of the [[connective tissue]], as the [[edema]] spreads extensively away from the [[infection]] site.
* [[Necrosis]] and [[hemorrhage]] occur. If initial [[inoculation]] has happened with minimal number of [[spores]], the primary lesion may be insignificant compared with that of the draining [[lymph node]]s
* [[Necrosis]] and [[hemorrhage]] occur. If initial [[inoculation]] has happened with minimal number of [[spores]], the primary lesion may be insignificant compared with that of the draining [[lymph node]]s.
* The [[bacilli]] migrate from the primary lesion, by means of the [[lymph vessel]]s, to the local [[lymph nodes]] where multiplication occurs, releasing a continuous stream of organisms and [[toxins]] into the efferent [[lymph vessel]]s and to the [[spleen]] and other lymphoid tissues where multiplication continues
* The [[bacilli]] migrate from the primary lesion, by means of the [[lymph vessel]]s, to the local [[lymph nodes]] where multiplication occurs, releasing a continuous stream of organisms and [[toxins]] into the efferent [[lymph vessel]]s and to the [[spleen]] and other lymphoid tissues where multiplication continues.
* In animals who died following [[subcutaneous]] challenge, the local [[lymph node]]s became [[hemorrhage|haemorrhagic]] and [[edema|edematous]]. [[Necrosis]] of lymphatic elements, and of [[blood vessel]] walls occur and [[phagocytosis]] of the [[bacilli]] is apparent
* In animals who died following [[subcutaneous]] challenge, the local [[lymph node]]s became [[hemorrhage|haemorrhagic]] and [[edema|edematous]]. [[Necrosis]] of lymphatic elements and of [[blood vessel]] walls occur and [[phagocytosis]] of the [[bacilli]] is apparent.
*  [[Septicemia]] often courses with [[splenic]] enlargement  
*  [[Septicemia]] often courses with [[splenic]] enlargement  


Injection anthrax will have similar [[pathogenesis]] to cutaneous anthrax, but since it is injected, it can spread throughout the body faster, and be harder to recognize and treat than the [[cutaneous]] form.<ref name=CDC>{{cite web | title = Anthrax Symptoms | url = http://www.cdc.gov/anthrax/basics/symptoms.html }}</ref>
Injection anthrax will have similar [[pathogenesis]] to cutaneous anthrax, but since it is injected, it can spread throughout the body faster and it becomes harder to recognize and treat than the [[cutaneous]] form.<ref name=CDC>{{cite web | title = Anthrax Symptoms | url = http://www.cdc.gov/anthrax/basics/symptoms.html }}</ref>


===Inhalation Anthrax===
===Inhalation Anthrax===
In inhalation anthrax, the inhaled [[spores]] will be deposited in the [[alveoli]] first. From there, they will be transported, within [[phagocytic cells]], through the [[lymphatic vessel]]s to the [[mediastinal]] [[lymph node]]s, where they will grow and cause [[hemorrhage|hemorrhagic]] [[lymphadenitis]]. [[Bacillus anthracis|Bacteria]] escape from the damaged [[lymph node]]s and invade the [[blood stream]] via the [[thoracic duct]]. Vegetative [[Bacillus]] then travel through the [[bloodstream]] and [[lymph vessel]]s, potentially causing [[septicemia]]. At the same time [[toxins]] are released, causing tissue damage and hampering the [[immune system]] to facilitate [[bacterial]] spread.<ref>{{cite book | last = Turnbull | first = Peter | title = Anthrax in humans and animals | publisher = World Health Organization | location = Geneva, Switzerland | year = 2008 | isbn = 9789241547536 }}</ref><ref name="pmid12610093">{{cite journal| author=Spencer RC| title=Bacillus anthracis. | journal=J Clin Pathol | year= 2003 | volume= 56 | issue= 3 | pages= 182-7 | pmid=12610093 | doi= | pmc=PMC1769905 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12610093  }} </ref><ref name="pmid8486963">{{cite journal| author=Friedlander AM, Welkos SL, Pitt ML, Ezzell JW, Worsham PL, Rose KJ et al.| title=Postexposure prophylaxis against experimental inhalation anthrax. | journal=J Infect Dis | year= 1993 | volume= 167 | issue= 5 | pages= 1239-43 | pmid=8486963 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8486963  }} </ref>
In inhalation anthrax, the inhaled [[spores]] will be deposited in the [[alveoli]] first. From there, they will be transported, within [[phagocytic cells]], through the [[lymphatic vessel]]s to the [[mediastinal]] [[lymph node]]s, where they will grow and cause [[hemorrhage|hemorrhagic]] [[lymphadenitis]]. [[Bacillus anthracis|Bacteria]] escape from the damaged [[lymph node]]s and invade the [[blood stream]] via the [[thoracic duct]]. Vegetative [[Bacillus]] then travel through the [[bloodstream]] and [[lymph vessel]]s, potentially causing [[septicemia]]. At the same time [[toxins]] are released, causing tissue damage and hampering the [[immune system]] to facilitate [[bacterial]] spread.<ref>{{cite book | last = Turnbull | first = Peter | title = Anthrax in humans and animals | publisher = World Health Organization | location = Geneva, Switzerland | year = 2008 | isbn = 9789241547536 }}</ref><ref name="pmid12610093">{{cite journal| author=Spencer RC| title=Bacillus anthracis. | journal=J Clin Pathol | year= 2003 | volume= 56 | issue= 3 | pages= 182-7 | pmid=12610093 | doi= | pmc=PMC1769905 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12610093  }} </ref><ref name="pmid8486963">{{cite journal| author=Friedlander AM, Welkos SL, Pitt ML, Ezzell JW, Worsham PL, Rose KJ et al.| title=Postexposure prophylaxis against experimental inhalation anthrax. | journal=J Infect Dis | year= 1993 | volume= 167 | issue= 5 | pages= 1239-43 | pmid=8486963 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8486963  }} </ref>


Once the [[bacteremia]] and associated [[toxemia]] reach a critical level, the severe [[symptoms]], characteristic of the acute phase of illness are manifested. During the acute phase, damage of the [[lung]] tissue becomes apparent on the [[X-ray]]. This damage results from the action of [[anthrax toxin]] on the [[endothelium]] of the lung’s [[capillary bed]]. Primary damage of the [[lung]] is not normally a feature of the initial phase of illness and primary [[pulmonary]] [[infection]] is an uncommon presentation.<ref>{{cite book | last = Turnbull | first = Peter | title = Anthrax in humans and animals | publisher = World Health Organization | location = Geneva, Switzerland | year = 2008 | isbn = 9789241547536 }}</ref><ref name="pmid12610093">{{cite journal| author=Spencer RC| title=Bacillus anthracis. | journal=J Clin Pathol | year= 2003 | volume= 56 | issue= 3 | pages= 182-7 | pmid=12610093 | doi= | pmc=PMC1769905 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12610093  }} </ref><ref name="pmid8486963">{{cite journal| author=Friedlander AM, Welkos SL, Pitt ML, Ezzell JW, Worsham PL, Rose KJ et al.| title=Postexposure prophylaxis against experimental inhalation anthrax. | journal=J Infect Dis | year= 1993 | volume= 167 | issue= 5 | pages= 1239-43 | pmid=8486963 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8486963  }} </ref>
Once the [[bacteremia]] and associated [[toxemia]] reach a critical level, the severe [[symptoms]] that are characteristic of the acute phase of illness are manifested. During the acute phase, damage of the [[lung]] tissue becomes apparent on the [[X-ray]]. This damage results from the action of [[anthrax toxin]] on the [[endothelium]] of the lung’s [[capillary bed]]. Primary damage of the [[lung]] is not normally a feature of the initial phase of illness and primary [[pulmonary]] [[infection]] is an uncommon presentation.<ref>{{cite book | last = Turnbull | first = Peter | title = Anthrax in humans and animals | publisher = World Health Organization | location = Geneva, Switzerland | year = 2008 | isbn = 9789241547536 }}</ref><ref name="pmid12610093">{{cite journal| author=Spencer RC| title=Bacillus anthracis. | journal=J Clin Pathol | year= 2003 | volume= 56 | issue= 3 | pages= 182-7 | pmid=12610093 | doi= | pmc=PMC1769905 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12610093  }} </ref><ref name="pmid8486963">{{cite journal| author=Friedlander AM, Welkos SL, Pitt ML, Ezzell JW, Worsham PL, Rose KJ et al.| title=Postexposure prophylaxis against experimental inhalation anthrax. | journal=J Infect Dis | year= 1993 | volume= 167 | issue= 5 | pages= 1239-43 | pmid=8486963 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8486963  }} </ref>


Studies in rhesus monkeys revealed that after [[spore]] [[inhalation]], its germination might take up to 60 days. This is the reason why [[antibiotic]] [[prophylaxis]] is recommended for 60 days.<ref name="pmid12610093">{{cite journal| author=Spencer RC| title=Bacillus anthracis. | journal=J Clin Pathol | year= 2003 | volume= 56 | issue= 3 | pages= 182-7 | pmid=12610093 | doi= | pmc=PMC1769905 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12610093  }} </ref>
Studies in rhesus monkeys revealed that after [[spore]] [[inhalation]], its germination might take up to 60 days. This is the reason why [[antibiotic]] [[prophylaxis]] is recommended for 60 days.<ref name="pmid12610093">{{cite journal| author=Spencer RC| title=Bacillus anthracis. | journal=J Clin Pathol | year= 2003 | volume= 56 | issue= 3 | pages= 182-7 | pmid=12610093 | doi= | pmc=PMC1769905 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12610093  }} </ref>


===Gastrointestinal Anthrax===
===Gastrointestinal Anthrax===
In animal studies, the [[intestinal]] lesions caused by ingested anthrax [[spores]] range from focal, to diffuse [[hemorrhage|hemorrhagic]], [[necrotic]] [[enteritis]] of the [[small intestine]]. The tendency for localized lesions to develop in [[Peyer's patches]] suggests a possible role of the [[M cell]] in the uptake of the anthrax [[bacillus]].<ref name=WHO>{{cite web | title = Anthrax in Humans and Animals | url = http://www.who.int/csr/resources/publications/anthrax_web.pdf }}</ref>
In animal studies, the [[intestinal]] lesions caused by ingested anthrax [[spores]] range from focal to diffuse [[hemorrhage|hemorrhagic]] [[necrotic]] [[enteritis]] of the [[small intestine]]. The tendency for localized lesions to develop in [[Peyer's patches]] suggests a possible role of the [[M cell]] in the uptake of the anthrax [[bacillus]].<ref name=WHO>{{cite web | title = Anthrax in Humans and Animals | url = http://www.who.int/csr/resources/publications/anthrax_web.pdf }}</ref>


==Gross Pathology==
==Gross Pathology==
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===Inhalational Anthrax===     
===Inhalational Anthrax===     
Gross pathologic lesions observed in non-human primates used in aerosol challenge models of inhalation anthrax include [[edema]], [[congestion]], [[hemorrhage]] and [[necrosis]] in the [[lungs]] and [[mediastinum]]. [[Splenitis]] and [[necrotizing]] or [[hemorrhage|hemorrhagic]] [[lymphadenitis]] involving the [[mediastinal]], [[tracheobronchial]], and other [[lymph nodes]] are common.<ref name="GuarnerJernigan2003">{{cite journal|last1=Guarner|first1=Jeannette|last2=Jernigan|first2=John A.|last3=Shieh|first3=Wun-Ju|last4=Tatti|first4=Kathleen|last5=Flannagan|first5=Lisa M.|last6=Stephens|first6=David S.|last7=Popovic|first7=Tanja|last8=Ashford|first8=David A.|last9=Perkins|first9=Bradley A.|last10=Zaki|first10=Sherif R.|title=Pathology and Pathogenesis of Bioterrorism-Related Inhalational Anthrax|journal=The American Journal of Pathology|volume=163|issue=2|year=2003|pages=701–709|issn=00029440|doi=10.1016/S0002-9440(10)63697-8}}</ref> Primary [[pulmonary]] lesions, including those of [[pneumonia]], are occasionally observed. [[Meningeal]] involvement ranging from [[edema]], [[congestion]], [[hemorrhage]], and [[necrosis]] to [[suppurative]] or [[hemorrhage|hemorrhagic]] [[meningitis]], usually secondary to hematogenous spread from other types of [[anthrax]], occurs in ≤77% of animals studied.<ref name="Twenhafel2010">{{cite journal|last1=Twenhafel|first1=N. A.|title=Pathology of Inhalational Anthrax Animal Models|journal=Veterinary Pathology|volume=47|issue=5|year=2010|pages=819–830|issn=0300-9858|doi=10.1177/0300985810378112}}</ref> Autopsy findings from persons who died from inhalation anthrax in Sverdlovsk and in the United States<ref>{{Cite journal| author = [[A. A. Abramova]] & [[L. M. Grinberg]] | title = &#91;Pathology of anthrax sepsis according to materials of the infectious outbreak in 1979 in Sverdlovsk (macroscopic changes)&#93; | journal = [[Arkhiv patologii]] | volume = 55 | issue = 1 | pages = 12–17 | year = 1993 | month = January-February | pmid = 7980032}}</ref> are consistent with findings from the non-human primates studies. Persons who died had extensive amounts of serosanguinous fluid in [[pleural]] cavities, [[edema]], and [[hemorrhage]] of the [[mediastinum]], and surrounding soft tissues. 48% had cerebral [[edema]], 21% had [[ascites]], 17% had [[pericardial effusion]]s, and 14% had [[petechial rash]]. [[Mediastinal]] [[lymph nodes]] and [[spleen]] also showed [[hemorrhage]] and [[necrosis]].<ref name="GuarnerJernigan2003">{{cite journal|last1=Guarner|first1=Jeannette|last2=Jernigan|first2=John A.|last3=Shieh|first3=Wun-Ju|last4=Tatti|first4=Kathleen|last5=Flannagan|first5=Lisa M.|last6=Stephens|first6=David S.|last7=Popovic|first7=Tanja|last8=Ashford|first8=David A.|last9=Perkins|first9=Bradley A.|last10=Zaki|first10=Sherif R.|title=Pathology and Pathogenesis of Bioterrorism-Related Inhalational Anthrax|journal=The American Journal of Pathology|volume=163|issue=2|year=2003|pages=701–709|issn=00029440|doi=10.1016/S0002-9440(10)63697-8}}</ref><ref>{{Cite journal| author = [[A. A. Abramova]] & [[L. M. Grinberg]] | title = &#91;Pathology of anthrax sepsis according to materials of the infectious outbreak in 1979 in Sverdlovsk (macroscopic changes)&#93; | journal = [[Arkhiv patologii]] | volume = 55 | issue = 1 | pages = 12–17 | year = 1993 | month = January-February | pmid = 7980032}}</ref>
Gross pathologic lesions observed in non-human primates used in aerosol challenge models of inhalation anthrax include [[edema]], [[congestion]], [[hemorrhage]], and [[necrosis]] in the [[lungs]] and [[mediastinum]]. [[Splenitis]] and [[necrotizing]] or [[hemorrhage|hemorrhagic]] [[lymphadenitis]] involving the [[mediastinal]], [[tracheobronchial]], and other [[lymph nodes]] are common.<ref name="GuarnerJernigan2003">{{cite journal|last1=Guarner|first1=Jeannette|last2=Jernigan|first2=John A.|last3=Shieh|first3=Wun-Ju|last4=Tatti|first4=Kathleen|last5=Flannagan|first5=Lisa M.|last6=Stephens|first6=David S.|last7=Popovic|first7=Tanja|last8=Ashford|first8=David A.|last9=Perkins|first9=Bradley A.|last10=Zaki|first10=Sherif R.|title=Pathology and Pathogenesis of Bioterrorism-Related Inhalational Anthrax|journal=The American Journal of Pathology|volume=163|issue=2|year=2003|pages=701–709|issn=00029440|doi=10.1016/S0002-9440(10)63697-8}}</ref> Primary [[pulmonary]] lesions, including those of [[pneumonia]], are occasionally observed. [[Meningeal]] involvement ranging from [[edema]], [[congestion]], [[hemorrhage]], and [[necrosis]] to [[suppurative]] or [[hemorrhage|hemorrhagic]] [[meningitis]], usually secondary to hematogenous spread from other types of [[anthrax]], occurs in ≤77% of animals studied.<ref name="Twenhafel2010">{{cite journal|last1=Twenhafel|first1=N. A.|title=Pathology of Inhalational Anthrax Animal Models|journal=Veterinary Pathology|volume=47|issue=5|year=2010|pages=819–830|issn=0300-9858|doi=10.1177/0300985810378112}}</ref> Autopsy findings from persons who died from inhalation anthrax in Sverdlovsk and in the United States<ref>{{Cite journal| author = [[A. A. Abramova]] & [[L. M. Grinberg]] | title = &#91;Pathology of anthrax sepsis according to materials of the infectious outbreak in 1979 in Sverdlovsk (macroscopic changes)&#93; | journal = [[Arkhiv patologii]] | volume = 55 | issue = 1 | pages = 12–17 | year = 1993 | month = January-February | pmid = 7980032}}</ref> are consistent with findings from the non-human primates studies. Persons who died had extensive amounts of serosanguinous fluid in [[pleural]] cavities, [[edema]], and [[hemorrhage]] of the [[mediastinum]] and surrounding soft tissues. 48% had cerebral [[edema]], 21% had [[ascites]], 17% had [[pericardial effusion]]s, and 14% had [[petechial rash]]. [[Mediastinal]] [[lymph nodes]] and [[spleen]] also showed [[hemorrhage]] and [[necrosis]].<ref name="GuarnerJernigan2003">{{cite journal|last1=Guarner|first1=Jeannette|last2=Jernigan|first2=John A.|last3=Shieh|first3=Wun-Ju|last4=Tatti|first4=Kathleen|last5=Flannagan|first5=Lisa M.|last6=Stephens|first6=David S.|last7=Popovic|first7=Tanja|last8=Ashford|first8=David A.|last9=Perkins|first9=Bradley A.|last10=Zaki|first10=Sherif R.|title=Pathology and Pathogenesis of Bioterrorism-Related Inhalational Anthrax|journal=The American Journal of Pathology|volume=163|issue=2|year=2003|pages=701–709|issn=00029440|doi=10.1016/S0002-9440(10)63697-8}}</ref><ref>{{Cite journal| author = [[A. A. Abramova]] & [[L. M. Grinberg]] | title = &#91;Pathology of anthrax sepsis according to materials of the infectious outbreak in 1979 in Sverdlovsk (macroscopic changes)&#93; | journal = [[Arkhiv patologii]] | volume = 55 | issue = 1 | pages = 12–17 | year = 1993 | month = January-February | pmid = 7980032}}</ref>


===Gastrointestinal Anthrax===
===Gastrointestinal Anthrax===
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===Cutaneous or Injection Anthrax===
===Cutaneous or Injection Anthrax===
[[Histologic]] examination of [[skin lesions]] caused by cutaneous anthrax revealed:<ref name="DixonMeselson1999">{{cite journal|last1=Dixon|first1=Terry C.|last2=Meselson|first2=Matthew|last3=Guillemin|first3=Jeanne|last4=Hanna|first4=Philip C.|title=Anthrax|journal=New England Journal of Medicine|volume=341|issue=11|year=1999|pages=815–826|issn=0028-4793|doi=10.1056/NEJM199909093411107}}</ref>
[[Histologic]] examination of [[skin lesions]] caused by cutaneous anthrax reveals:<ref name="DixonMeselson1999">{{cite journal|last1=Dixon|first1=Terry C.|last2=Meselson|first2=Matthew|last3=Guillemin|first3=Jeanne|last4=Hanna|first4=Philip C.|title=Anthrax|journal=New England Journal of Medicine|volume=341|issue=11|year=1999|pages=815–826|issn=0028-4793|doi=10.1056/NEJM199909093411107}}</ref>
* Tissue [[necrosis]]
* Tissue [[necrosis]]
* [[Edema]]
* [[Edema]]
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===Inhalation Anthrax===
===Inhalation Anthrax===
[[Histologic]] evaluation of affected tissues revealed:
Histologic evaluation of affected tissues reveals:
* Numerous [[necrotic]] foci of [[hemorrhage]] in the [[mediastinum]] or [[hilar]] and peribronchial [[lymph nodes]]
* Numerous [[necrotic]] foci of [[hemorrhage]] in the [[mediastinum]] or [[hilar]] and peribronchial [[lymph nodes]]
* [[Pulmonary]] [[infection]] may also result in interstitial [[pneumonia]] associated with:
* [[Pulmonary]] [[infection]] may also result in interstitial [[pneumonia]] associated with:
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Image:CutaneousA56.jpg| Micrograph revealing submucosal hemorrhage in the small intestine, in a case of fatal human anthrax; H&E stain; Mg. 240X.”<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:CutaneousA56.jpg| Micrograph revealing submucosal hemorrhage in the small intestine, in a case of fatal human anthrax; H&E stain; Mg. 240X.”<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:CutaneousA57.jpg| <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:CutaneousA57.jpg| "Meningeal infection due to Bacillus anthracis bacteria using an H&E 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:CutaneousA61.jpg| Symptoms of cutaneous anthrax due to B. anthracis.” <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:CutaneousA63.jpg| "Blood agar culture plate growing B. anthracis and other soil flora.” <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:CutaneousA62.jpg| Blood agar culture plate growing B. anthracis and other soil flora.”<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:CutaneousA63.jpg| Hematoxylin-eosin stained (H&E) stained photomicrograph revealing some of the histopathologic changes associated with this Bacillus anthracis bacterial 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:CutaneousA65.jpg| Brain section through the ventricles revealing an inter ventricular hemorrhage as consequence of virulence factors of Bacillus anthracis (edema toxin, lethal toxin, and antiphagocytic capsular antigen). The toxins are responsible for the primary clinical manifestations of hemorrhage, edema, and necrosis”<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:CutaneousA65.jpg| Brain section through the ventricles revealing an inter ventricular hemorrhage as consequence of virulence factors of Bacillus anthracis (edema toxin, lethal toxin, and antiphagocytic capsular antigen). The toxins are responsible for the primary clinical manifestations of hemorrhage, edema, and necrosis”<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>
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Image:CutaneousA68.jpg| Cutaneous anthrax lesion on the arm of a 50 year old female.”<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:CutaneousA68.jpg| Cutaneous anthrax lesion on the arm of a 50 year old female.”<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:CutaneousA69.jpg| High magnification of 12,483X, this scanning electron micrograph (SEM) depicted spores from the Sterne strain of Bacillus anthracis bacteria.”<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:CutaneousA70.jpg| "Magnification of 12,483X, this scanning electron micrograph (SEM) depicted spores from the Sterne strain of Bacillus anthracis bacteria. ”<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:CutaneousA70.jpg| "Magnification of 12,483X, this scanning electron micrograph (SEM) depicted spores from the Sterne strain of Bacillus anthracis bacteria. ”<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>
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Image:CutaneousA77.jpg| "Photomicrograph demonstrating a positive Gram stain with Bacillus anthracis”<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:CutaneousA77.jpg| "Photomicrograph demonstrating a positive Gram stain with Bacillus anthracis”<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:Milzbrand.jpg| "Anthrax lesion on the skin of the forearm caused by the bacterium Bacillus anthracis”<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:CutaneousA79.jpg| "Anthrax lesion on the neck”<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:Anthrax-6.jpg| "Anthrax lesion on volar surface of right forearm”<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:CutaneousA80.jpg| "Bacillus anthracis tenacity positive on sheep blood agar.”<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:CutaneousA80.jpg| "Bacillus anthracis tenacity positive on sheep blood agar.”<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>
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Image:CutaneousA105.jpg| "Numerous rod-shaped Bacillus anthracis bacteria, some that had linked together to form chains, while others remained solitary”<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:CutaneousA105.jpg| "Numerous rod-shaped Bacillus anthracis bacteria, some that had linked together to form chains, while others remained solitary”<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:CutaneousA106.jpg| "Anthrax, skin of left forearm”<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:CutaneousA107.jpg| "Anthrax, skin of right forearm, 4th day”<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:CutaneousA108.jpg| "Necrosis of lymph node due to anthrax”<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:CutaneousA108.jpg| "Necrosis of lymph node due to anthrax”<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:CutaneousA109.jpg| "Anthrax, skin of face, 13th day”<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:CutaneousA110.jpg| "Anthrax, skin of face, 11th day”<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:CutaneousA111.jpg| "Anthrax, skin of face, 8th day”<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:CutaneousA112.jpg| "Anthrax, skin of face, 6th day”<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:CutaneousA113.jpg| "Anthrax, skin of face, 4th day”<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:CutaneousA114.jpg| "Anthrax, skin of right forearm, 7th day.”<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:CutaneousA115.jpg| "Anthrax, skin of right forearm, 5th day”<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:CutaneousA116.jpg| "Anthrax, skin of right forearm, 12th day.”<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:CutaneousA118.jpg| "Cutaneous anthrax lesion on neck of man”<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:CutaneousA119.jpg| "Cutaneous anthrax, lesion on the left forearm”<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:CutaneousA120.jpg| "Bacillus anthracis from agar culture <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:CutaneousA120.jpg| "Bacillus anthracis from agar culture <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>
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Image:CutaneousA132.jpg| "Gross pathology of fixed, cut brain showing hemorrhagic meningitis due to inhalation anthrax.”<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:CutaneousA132.jpg| "Gross pathology of fixed, cut brain showing hemorrhagic meningitis due to inhalation anthrax.”<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:CutaneousA133.jpg| "Anthrax skin lesion on face of man. Cutaneous”<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:CutaneousA134.jpg| "Anthrax skin lesion on neck of man. Cutaneous”<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:CutaneousA135.jpg| "Gram-stained photomicrograph revealing numerous rod-shaped Bacillus anthracis bacteria that had linked together to form long filamentous chains.” <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:CutaneousA135.jpg| "Gram-stained photomicrograph revealing numerous rod-shaped Bacillus anthracis bacteria that had linked together to form long filamentous chains.” <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>
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Image:CutaneousA137.jpg| "Hematoxylin-eosin (H&E)-stained photomicrograph of a small intestinal tissue sample revealed the presence of histopathologic changes indicative of marked mucosal and submucosal hemorrhage, with accompanying arteriolar degeneration in a case of fatal human anthrax.” <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:CutaneousA137.jpg| "Hematoxylin-eosin (H&E)-stained photomicrograph of a small intestinal tissue sample revealed the presence of histopathologic changes indicative of marked mucosal and submucosal hemorrhage, with accompanying arteriolar degeneration in a case of fatal human anthrax.” <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:CutaneousA138.jpg| "Hematoxylin-eosin (H&E)-stained photomicrograph of a meningeal tissue sample revealed the presence of histopathologic changes indicative of hemorrhagic meningitis in a case of fatal human anthrax.”  <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:CutaneousA138.jpg| "Hematoxylin-eosin (H&E)-stained photomicrograph of a meningeal tissue sample revealed the presence of histopathologic changes indicative of hemorrhagic meningitis in a case of fatal human anthrax.”  <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>
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[[Category:Zoonoses]]
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[[Category:Medical disasters]]
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[[Category:Infectious disease]]
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Latest revision as of 20:25, 29 July 2020

Anthrax Microchapters

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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

The genetic material of Bacillus anthracis is coded within 1 chromosome and 2 plasmids, which are fundamental for its toxicity. The spores of B. anthracis are the infectious form and can remain dormant in the environment for decades. The disease may be transmitted through the skin, gastrointestinal or respiratory systems. The bacterium causes disease through 2 mechanisms: toxemia and bacterial infection.[1] B. anthracis begins to produce toxins within hours of germination.[2] Protective antigen (PA) and edema factor (EF) combine to form edema toxin (ET), and PA and lethal factor (LF) combine to form lethal toxin (LT), the active toxins. Bacterial toxins have a direct cytotoxic effect by interfering with cellular pathways, being also responsible for weakening the immune system, so the initial systemic infection may occur. Anthrax lesions at any site are characterized by lymphadenopathy, extensive edema, necrosis and confluent exudate containing macrophages and neutrophils. If not stopped, the infection may affect different organs, causing septicemia and potentially death.

Genetics

The genetic component of Bacillus anthracis includes 1 chromosome and 2 plasmids. These plasmids (pXO1 and pXO2) are fundamental for its toxicity:[1]

  • pXO1 - encodes 3 components of the anthrax exotoxins:
  • Protective Antigen (PA)
  • Lethal Factor (LF)
  • Edema Factor (EF)

Transmission

The route of transmission of anthrax allows for its classification into the following:[3]

  • Cutaneous anthrax - commonly requires a prior skin lesion as a prerequisite for infection
  • Gastrointestinal anthrax - contracted following ingestion of contaminated food, primarily meat from an animal that died of the disease, or conceivably from ingestion of contaminated water
  • Inhalational anthrax - from breathing in airborne anthrax spores
  • Injection anthrax - from the injection of a drug containing or contaminated with Bacillus anthracis

Pathogenesis

B. anthracis, the causative agent of anthrax, is a spore-forming bacterium. The spores of B. anthracis, which can remain dormant in the environment for decades, are the infectious form, but this vegetative form of B. anthracis rarely causes disease.[4] The bacterium causes disease through 2 mechanisms: toxemia and bacterial infection.[1] Spores introduced through the skin lead to cutaneous or injection anthrax; those introduced through the gastrointestinal tract lead to gastrointestinal anthrax; and those introduced through the lungs lead to inhalation anthrax. After entering a human or animal, B. anthracis spores are believed to germinate locally or be phagocytosed by dendritic cells and macrophages. These will then carry the spores to the lymph nodes, where they germinate.[5][1] B. anthracis begins to produce toxins within hours of germination.[2] Protective antigen (PA) and edema factor (EF) combine to form edema toxin (ET), and PA and lethal factor (LF) combine to form lethal toxin (LT). After binding to surface receptors, the PA portion of the complexes facilitates translocation of the toxins to the cytosol, in which EF and LF exert their toxic effects.[6] Bacillus anthracis disseminate to multiple organs including spleen, liver, intestines, kidneys, adrenal glands, and meninges, affecting their normal functions and leading to systemic infection with a potentially fatal outcome.[7][8][3]

The virulence factors of Bacillus anthracis are:

  • PA
  • LF
  • EF

Bacterial Toxins

In order to infect the body, Bacillus anthracis must produce toxins. These toxins have 3 main toxic effects: edema, hemorrhage, and necrosis. Besides their direct toxic effects responsible for tissue damage, anthrax toxins are also responsible for interfering with cellular pathways, in such way that defense functions of the host's immune system are affected. This will ultimately allow initial systemic infection by interfering with the immune system.[1]

When isolated, the 3 structural elements of the anthrax exotoxins are non-toxic. However, when combined, they form virulent exotoxins:[1]

  • LF + PA = LT (Lethal Toxin)
  • EF + PA = ET (Edema Toxin)

The PA is responsible for attaching the toxin to the cell, while the LF and the EF are responsible for the toxicity.[1]

After germinating, B. anthracis produces and releases into the blood stream PA, LF, and EF toxins separately. However, PA is secreted in its inactivated form (PA). In order to form the exotoxin complexes with LF and EF, it must first be activated by host-cellular receptors:[1]

  • CMG2 - Capillary Morphogenesis Protein 2 (predominant toxin receptorin vivo)
  • TEM8 - Tumor Endothelium Marker 8 (minor role)

CMG2 and TEM8 cleave PA into PA20 and PA63. PA63 (a C-terminal fragment) is the activated form of PA, responsible for combining with EF and LF, thereby creating the toxin oligomer PA63 oligomer receptor complex. This complex will be internalized via receptor mediated endocytosis within an endosome.[1]

The acidic environment within the endosomes leads to the formation of a channel called PA63 oligomer channel, on the endosomal membrane. LF and EF are then released in the cytosol of the host cell, to then exert their toxic effects.[1]

After experiments in mice, edema toxin was noted to be the major virulence factor since it caused death of mice in much lesser dosages than lethal toxin.

  • Edema toxin is a calmodulin-dependent adenylyl cyclase, known to increase intracellular cAMP through the conversion of ATP into cAMP, thus affecting several intracellular pathways.
  • Lethal toxin is a zinc-dependent metaloproteinase known to interfere with the mitogen-activated protein kinase (MEK), thereby hampering multiple intracellular mechanisms.[1]

Cutaneous or Injection Anthrax

According to animal studies, spores that enter the skin of susceptible animals (either through a lesion or by injection) germinate and give rise, in about 2 - 4 hours, to a small edematous area containing capsulated bacilli. The following stages are noticed:[3]

Injection anthrax will have similar pathogenesis to cutaneous anthrax, but since it is injected, it can spread throughout the body faster and it becomes harder to recognize and treat than the cutaneous form.[9]

Inhalation Anthrax

In inhalation anthrax, the inhaled spores will be deposited in the alveoli first. From there, they will be transported, within phagocytic cells, through the lymphatic vessels to the mediastinal lymph nodes, where they will grow and cause hemorrhagic lymphadenitis. Bacteria escape from the damaged lymph nodes and invade the blood stream via the thoracic duct. Vegetative Bacillus then travel through the bloodstream and lymph vessels, potentially causing septicemia. At the same time toxins are released, causing tissue damage and hampering the immune system to facilitate bacterial spread.[10][11][12]

Once the bacteremia and associated toxemia reach a critical level, the severe symptoms that are characteristic of the acute phase of illness are manifested. During the acute phase, damage of the lung tissue becomes apparent on the X-ray. This damage results from the action of anthrax toxin on the endothelium of the lung’s capillary bed. Primary damage of the lung is not normally a feature of the initial phase of illness and primary pulmonary infection is an uncommon presentation.[13][11][12]

Studies in rhesus monkeys revealed that after spore inhalation, its germination might take up to 60 days. This is the reason why antibiotic prophylaxis is recommended for 60 days.[11]

Gastrointestinal Anthrax

In animal studies, the intestinal lesions caused by ingested anthrax spores range from focal to diffuse hemorrhagic necrotic enteritis of the small intestine. The tendency for localized lesions to develop in Peyer's patches suggests a possible role of the M cell in the uptake of the anthrax bacillus.[3]

Gross Pathology

Cutaneous and Injection Anthrax

Cutaneous infection typically produces ulcerated lesions which are covered by a scab and often contain numerous microorganisms. Anthrax eschars are generally seen on exposed unprotected regions of the body, mostly on the face, neck, hands and wrists. Generally cutaneous lesions are single, but sometimes two or more lesions are present.[14][15]

The lesions produced by injection anthrax will be similar to the ones of the cutaneous form. The difference will reside on the fact that injection anthrax can spread throughout the body faster and be harder to recognize and treat than cutaneous anthrax.[9]

Inhalational Anthrax

Gross pathologic lesions observed in non-human primates used in aerosol challenge models of inhalation anthrax include edema, congestion, hemorrhage, and necrosis in the lungs and mediastinum. Splenitis and necrotizing or hemorrhagic lymphadenitis involving the mediastinal, tracheobronchial, and other lymph nodes are common.[16] Primary pulmonary lesions, including those of pneumonia, are occasionally observed. Meningeal involvement ranging from edema, congestion, hemorrhage, and necrosis to suppurative or hemorrhagic meningitis, usually secondary to hematogenous spread from other types of anthrax, occurs in ≤77% of animals studied.[17] Autopsy findings from persons who died from inhalation anthrax in Sverdlovsk and in the United States[18] are consistent with findings from the non-human primates studies. Persons who died had extensive amounts of serosanguinous fluid in pleural cavities, edema, and hemorrhage of the mediastinum and surrounding soft tissues. 48% had cerebral edema, 21% had ascites, 17% had pericardial effusions, and 14% had petechial rash. Mediastinal lymph nodes and spleen also showed hemorrhage and necrosis.[16][19]

Gastrointestinal Anthrax

On gastrointestinal infection the typical eschar may occur on different locations, including:[11]

According to the location of the eschar, gastrointestinal anthrax may be divided in 2 categories: oropharyngeal and abdominal.[11]

As the eschar progresses, symptoms will appear as a result of the necrosis of the lesion, coupled with severe intestinal and mesenteric edema and lymph node enlargement in the mesentery.[11]

Microscopic Pathology

Anthrax lesions at any site are characterized by extensive necrosis and confluent exudate, containing macrophages and neutrophils. In histopathological specimens or culture media, the presence of large boxcar-shaped Gram-positive bacilli in chains suggests the diagnosis.

Cutaneous or Injection Anthrax

Histologic examination of skin lesions caused by cutaneous anthrax reveals:[20]

Inhalation Anthrax

Histologic evaluation of affected tissues reveals:

Gastrointestinal Anthrax

Histologic evaluation of affected tissues revealed:[20]

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 Liu, Shihui; Moayeri, Mahtab; Leppla, Stephen H. (2014). "Anthrax lethal and edema toxins in anthrax pathogenesis". Trends in Microbiology. 22 (6): 317–325. doi:10.1016/j.tim.2014.02.012. ISSN 0966-842X.
  2. 2.0 2.1 Hanna, Philip C.; Ireland, John A.W. (1999). "Understanding Bacillus anthracis pathogenesis". Trends in Microbiology. 7 (5): 180–182. doi:10.1016/S0966-842X(99)01507-3. ISSN 0966-842X.
  3. 3.0 3.1 3.2 3.3 "Anthrax in Humans and Animals" (PDF).
  4. Shadomy, Sean V.; Smith, Theresa L. (2008). "Anthrax". Journal of the American Veterinary Medical Association. 233 (1): 63–72. doi:10.2460/javma.233.1.63. ISSN 0003-1488.
  5. Ross, Joan M. (1957). "The pathogenesis of anthrax following the administration of spores by the respiratory route". The Journal of Pathology and Bacteriology. 73 (2): 485–494. doi:10.1002/path.1700730219. ISSN 0368-3494.
  6. Moayeri, M (2004). "The roles of anthrax toxin in pathogenesis". Current Opinion in Microbiology. 7 (1): 19–24. doi:10.1016/j.mib.2003.12.001. ISSN 1369-5274.
  7. Rubin, Raphael (2012). Rubin's pathology : clinicopathologic foundations of medicine. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 1605479683.
  8. Kumar, Vinay (2014). Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Elsevier/Saunders. ISBN 0323266169.
  9. 9.0 9.1 "Anthrax Symptoms".
  10. Turnbull, Peter (2008). Anthrax in humans and animals. Geneva, Switzerland: World Health Organization. ISBN 9789241547536.
  11. 11.0 11.1 11.2 11.3 11.4 11.5 Spencer RC (2003). "Bacillus anthracis". J Clin Pathol. 56 (3): 182–7. PMC 1769905. PMID 12610093.
  12. 12.0 12.1 Friedlander AM, Welkos SL, Pitt ML, Ezzell JW, Worsham PL, Rose KJ; et al. (1993). "Postexposure prophylaxis against experimental inhalation anthrax". J Infect Dis. 167 (5): 1239–43. PMID 8486963.
  13. Turnbull, Peter (2008). Anthrax in humans and animals. Geneva, Switzerland: World Health Organization. ISBN 9789241547536.
  14. Rubin, Raphael (2012). Rubin's pathology : clinicopathologic foundations of medicine. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 1605479683.
  15. Kumar, Vinay (2014). Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Elsevier/Saunders. ISBN 0323266169.
  16. 16.0 16.1 Guarner, Jeannette; Jernigan, John A.; Shieh, Wun-Ju; Tatti, Kathleen; Flannagan, Lisa M.; Stephens, David S.; Popovic, Tanja; Ashford, David A.; Perkins, Bradley A.; Zaki, Sherif R. (2003). "Pathology and Pathogenesis of Bioterrorism-Related Inhalational Anthrax". The American Journal of Pathology. 163 (2): 701–709. doi:10.1016/S0002-9440(10)63697-8. ISSN 0002-9440.
  17. Twenhafel, N. A. (2010). "Pathology of Inhalational Anthrax Animal Models". Veterinary Pathology. 47 (5): 819–830. doi:10.1177/0300985810378112. ISSN 0300-9858.
  18. A. A. Abramova & L. M. Grinberg (1993). "[Pathology of anthrax sepsis according to materials of the infectious outbreak in 1979 in Sverdlovsk (macroscopic changes)]". Arkhiv patologii. 55 (1): 12–17. PMID 7980032. Unknown parameter |month= ignored (help)
  19. A. A. Abramova & L. M. Grinberg (1993). "[Pathology of anthrax sepsis according to materials of the infectious outbreak in 1979 in Sverdlovsk (macroscopic changes)]". Arkhiv patologii. 55 (1): 12–17. PMID 7980032. Unknown parameter |month= ignored (help)
  20. 20.0 20.1 Dixon, Terry C.; Meselson, Matthew; Guillemin, Jeanne; Hanna, Philip C. (1999). "Anthrax". New England Journal of Medicine. 341 (11): 815–826. doi:10.1056/NEJM199909093411107. ISSN 0028-4793.
  21. 21.000 21.001 21.002 21.003 21.004 21.005 21.006 21.007 21.008 21.009 21.010 21.011 21.012 21.013 21.014 21.015 21.016 21.017 21.018 21.019 21.020 21.021 21.022 21.023 21.024 21.025 21.026 21.027 21.028 21.029 21.030 21.031 21.032 21.033 21.034 21.035 21.036 21.037 21.038 21.039 21.040 21.041 21.042 21.043 21.044 21.045 21.046 21.047 21.048 21.049 21.050 21.051 21.052 21.053 21.054 21.055 21.056 21.057 21.058 21.059 21.060 21.061 21.062 21.063 21.064 21.065 21.066 21.067 21.068 21.069 21.070 21.071 21.072 21.073 21.074 21.075 21.076 21.077 21.078 21.079 21.080 21.081 21.082 21.083 21.084 21.085 21.086 21.087 21.088 21.089 21.090 21.091 21.092 21.093 21.094 21.095 21.096 21.097 21.098 21.099 21.100 21.101 21.102 21.103 21.104 21.105 21.106 21.107 21.108 21.109 21.110 21.111 21.112 21.113 21.114 "Public Health Image Library (PHIL), Centers for Disease Control and Prevention".

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