Leptospirosis pathophysiology: Difference between revisions

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{{CMG}}; {{AE}}{{VSKP}}
{{CMG}}; {{AE}}{{VSKP}}
==Overview==
==Overview==
Leptospires shed in the urine of animals to the environment from where humans are infected by incidental hosts. In Carriers these bacteria harbour in the [[renal tubules]] and can persist in soil or surface water and then transmits to human hosts via mucous membranes or abraded skin.<ref name="pmid13559904">{{cite journal| author=BABUDIERI B| title=Animal reservoirs of leptospires. | journal=Ann N Y Acad Sci | year= 1958 | volume= 70 | issue= 3 | pages= 393-413 | pmid=13559904 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13559904  }} </ref><ref name="ForbesZochowski2012">{{cite journal|last1=Forbes|first1=A. E.|last2=Zochowski|first2=W. J.|last3=Dubrey|first3=S. W.|last4=Sivaprakasam|first4=V.|title=Leptospirosis and Weil's disease in the UK|journal=QJM|volume=105|issue=12|year=2012|pages=1151–1162|issn=1460-2725|doi=10.1093/qjmed/hcs145}}</ref> Pathogen transmit through various mechanisms such as broken skin, mucus membranes and the conjunctivae, exposure to contaminated water are at risk of contracting leptospirosis.<ref name="pmid22843698">{{cite journal| author=Forbes AE, Zochowski WJ, Dubrey SW, Sivaprakasam V| title=Leptospirosis and Weil's disease in the UK. | journal=QJM | year= 2012 | volume= 105 | issue= 12 | pages= 1151-62 | pmid=22843698 | doi=10.1093/qjmed/hcs145 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22843698  }} </ref>
Leptospires shed in the [[urine]] of animals to the environment from where humans are infected by incidental hosts. In Carriers these [[bacteria]] harbor in the [[renal tubules]] and can persist in soil or surface water and then transmits to human hosts via [[mucous membranes]] or abraded skin.<ref name="pmid13559904">{{cite journal| author=BABUDIERI B| title=Animal reservoirs of leptospires. | journal=Ann N Y Acad Sci | year= 1958 | volume= 70 | issue= 3 | pages= 393-413 | pmid=13559904 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13559904  }} </ref><ref name="ForbesZochowski2012">{{cite journal|last1=Forbes|first1=A. E.|last2=Zochowski|first2=W. J.|last3=Dubrey|first3=S. W.|last4=Sivaprakasam|first4=V.|title=Leptospirosis and Weil's disease in the UK|journal=QJM|volume=105|issue=12|year=2012|pages=1151–1162|issn=1460-2725|doi=10.1093/qjmed/hcs145}}</ref> [[Pathogen]] transmit through various mechanisms such as broken [[skin]], mucus membranes and the conjunctivae, exposure to contaminated water are at risk of contracting leptospirosis.<ref name="pmid22843698">{{cite journal| author=Forbes AE, Zochowski WJ, Dubrey SW, Sivaprakasam V| title=Leptospirosis and Weil's disease in the UK. | journal=QJM | year= 2012 | volume= 105 | issue= 12 | pages= 1151-62 | pmid=22843698 | doi=10.1093/qjmed/hcs145 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22843698  }} </ref>
 
==Pathophysiology==
The disease leptospirosis involves a spectrum of symptoms ranging from subclinical infection to a severe syndrome of multiorgan infection with high mortality and Weil’s disease represents only the most severe presentation. Severe leptospirosis is frequently caused by serovars of the icterohaemorrhagiae serogroup. The presentation of leptospirosis is biphasic, with the acute or septicemic phase lasting about a week, followed by the immune phase, characterized by antibody production and excretion of leptospires in the urine.<ref name="Levett2001">{{cite journal|last1=Levett|first1=P. N.|title=Leptospirosis|journal=Clinical Microbiology Reviews|volume=14|issue=2|year=2001|pages=296–326|issn=0893-8512|doi=10.1128/CMR.14.2.296-326.2001}}</ref>


==Pathogenesis==
The disease [[leptospirosis]] involves a spectrum of symptoms ranging from subclinical infection to a severe syndrome of multiorgan infection with high mortality and Weil’s disease represents only the most severe presentation. Severe leptospirosis is frequently caused by serovars of the icterohaemorrhagiae serogroup. The presentation of leptospirosis is biphasic, with the acute or septicemic phase lasting about a week, followed by the immune phase, characterized by antibody production and excretion of leptospires in the urine.<ref name="Levett2001">{{cite journal|last1=Levett|first1=P. N.|title=Leptospirosis|journal=Clinical Microbiology Reviews|volume=14|issue=2|year=2001|pages=296–326|issn=0893-8512|doi=10.1128/CMR.14.2.296-326.2001}}</ref>
=== Reservoirs ===
=== Reservoirs ===
The major reservoir for leptospirosis is rat and small rodents that appear to harbour more virulent strains of the disease.<ref name="Picardeau2013">{{cite journal|last1=Picardeau|first1=M.|title=Diagnosis and epidemiology of leptospirosis|journal=Médecine et Maladies Infectieuses|volume=43|issue=1|year=2013|pages=1–9|issn=0399077X|doi=10.1016/j.medmal.2012.11.005}}</ref>
The major reservoir for leptospirosis is rat and small rodents that appear to harbour more virulent strains of the disease.<ref name="Picardeau2013">{{cite journal|last1=Picardeau|first1=M.|title=Diagnosis and epidemiology of leptospirosis|journal=Médecine et Maladies Infectieuses|volume=43|issue=1|year=2013|pages=1–9|issn=0399077X|doi=10.1016/j.medmal.2012.11.005}}</ref>
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Domestic animals such as dogs,cattle and pigs acts as potential carriers that increases the risk of leptospirosis in humans. These carriers are generally asymptomatic.<ref name="pmid19011247">{{cite journal| author=Gaudie CM, Featherstone CA, Phillips WS, McNaught R, Rhodes PM, Errington J et al.| title=Human Leptospira interrogans serogroup icterohaemorrhagiae infection (Weil's disease) acquired from pet rats. | journal=Vet Rec | year= 2008 | volume= 163 | issue= 20 | pages= 599-601 | pmid=19011247 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19011247  }} </ref><ref name="pmid19202179">{{cite journal| author=Strugnell BW, Featherstone C, Gent M, Lister P, Evans G, Okereke E et al.| title=Weil's disease associated with the adoption of a feral rat. | journal=Vet Rec | year= 2009 | volume= 164 | issue= 6 | pages= 186 | pmid=19202179 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19202179  }} </ref>
Domestic animals such as dogs,cattle and pigs acts as potential carriers that increases the risk of leptospirosis in humans. These carriers are generally asymptomatic.<ref name="pmid19011247">{{cite journal| author=Gaudie CM, Featherstone CA, Phillips WS, McNaught R, Rhodes PM, Errington J et al.| title=Human Leptospira interrogans serogroup icterohaemorrhagiae infection (Weil's disease) acquired from pet rats. | journal=Vet Rec | year= 2008 | volume= 163 | issue= 20 | pages= 599-601 | pmid=19011247 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19011247  }} </ref><ref name="pmid19202179">{{cite journal| author=Strugnell BW, Featherstone C, Gent M, Lister P, Evans G, Okereke E et al.| title=Weil's disease associated with the adoption of a feral rat. | journal=Vet Rec | year= 2009 | volume= 164 | issue= 6 | pages= 186 | pmid=19202179 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19202179  }} </ref>


===Transmission===
=== Modes of transmission ===
Infection can occurs either by direct contact with the carrier’s urine or through indirect transmission via urine-contaminated environment. Infection due to direct transmission through direct oral intake of contaminated drinking water or food is very rare.<ref name="pmid3618584">{{cite journal| author=Cacciapuoti B, Ciceroni L, Maffei C, Di Stanislao F, Strusi P, Calegari L et al.| title=A waterborne outbreak of leptospirosis. | journal=Am J Epidemiol | year= 1987 | volume= 126 | issue= 3 | pages= 535-45 | pmid=3618584 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3618584  }} </ref> Pathogenic leptospires live in the renal system and the genital tracts of domestic animals which act as sites of persistence.<ref name="pmid4081333">{{cite journal| author=Ellis WA, O'Brien JJ, Cassells JA, Neill SD, Hanna J| title=Excretion of Leptospira interrogans serovar hardjo following calving or abortion. | journal=Res Vet Sci | year= 1985 | volume= 39 | issue= 3 | pages= 296-8 | pmid=4081333 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4081333  }} </ref><ref name="pmid3705357">{{cite journal| author=Ellis WA, McParland PJ, Bryson DG, Thiermann AB, Montgomery J| title=Isolation of leptospires from the genital tract and kidneys of aborted sows. | journal=Vet Rec | year= 1986 | volume= 118 | issue= 11 | pages= 294-5 | pmid=3705357 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3705357  }} </ref> Bacteria shed from the infected animals such as rodents and domesticat animals through urine. These animals may not show signs of disease, but humans shows signs of illness after contact with infected urine, or through contact with water, soil or food that has been contaminated and the outbreaks are associates with floodwaters. The major route of infection by leptospires is probably by transmission through indirect contact with leptospires secreted into the environment. Humans are considered dead end hosts, but sometimes they also act as carriers. Mammalian species (e.g. rodents, insectivores, dogs, pigs and cattle) act as the main carriers of the disease.<ref name="pmid20186328">{{cite journal| author=Ganoza CA, Matthias MA, Saito M, Cespedes M, Gotuzzo E, Vinetz JM| title=Asymptomatic renal colonization of humans in the peruvian Amazon by Leptospira. | journal=PLoS Negl Trop Dis | year= 2010 | volume= 4 | issue= 2 | pages= e612 | pmid=20186328 | doi=10.1371/journal.pntd.0000612 | pmc=2826405 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20186328  }} </ref>
# Direct contact with [[urine]] or [[tissue]] of [[infected]] animal: Through [[skin]] [[abrasions]] and intact [[Mucous membrane|mucus membrane]]
Leptospires are excreted in urine into the environment, where they can survive for several months, depending on favourable environmental conditions such as humid and temperate areas. The pathogen may also be excreted in the products of abortion in mammalian animal species.<ref name="pmid4081333">{{cite journal| author=Ellis WA, O'Brien JJ, Cassells JA, Neill SD, Hanna J| title=Excretion of Leptospira interrogans serovar hardjo following calving or abortion. | journal=Res Vet Sci | year= 1985 | volume= 39 | issue= 3 | pages= 296-8 | pmid=4081333 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4081333  }} </ref>
# Indirect contact: Broken skin with infected soil, water or vegetation, Through ingestion of contaminated food and water
# [[Droplet]] [[infection]]: Inhalation of droplets of infected urine
Infection can occurs either by direct contact with the carrier’s urine or through indirect transmission via urine-contaminated environment. Infection due to direct transmission through direct [[oral]] intake of contaminated drinking water or food is very rare.<ref name="pmid3618584">{{cite journal| author=Cacciapuoti B, Ciceroni L, Maffei C, Di Stanislao F, Strusi P, Calegari L et al.| title=A waterborne outbreak of leptospirosis. | journal=Am J Epidemiol | year= 1987 | volume= 126 | issue= 3 | pages= 535-45 | pmid=3618584 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3618584  }} </ref> Pathogenic leptospires live in the [[renal system]] and the [[genital]] tracts of domestic animals which act as sites of persistence.<ref name="pmid4081333">{{cite journal| author=Ellis WA, O'Brien JJ, Cassells JA, Neill SD, Hanna J| title=Excretion of Leptospira interrogans serovar hardjo following calving or abortion. | journal=Res Vet Sci | year= 1985 | volume= 39 | issue= 3 | pages= 296-8 | pmid=4081333 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4081333  }} </ref><ref name="pmid3705357">{{cite journal| author=Ellis WA, McParland PJ, Bryson DG, Thiermann AB, Montgomery J| title=Isolation of leptospires from the genital tract and kidneys of aborted sows. | journal=Vet Rec | year= 1986 | volume= 118 | issue= 11 | pages= 294-5 | pmid=3705357 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3705357  }} </ref> [[Bacteria]] shed from the [[infected]] animals such as rodents and domesticat animals through urine. These animals may not show signs of disease but humans shows signs of [[illness]] after contact with [[infected]] [[urine]], or through contact with water, soil or food that has been contaminated and the [[outbreaks]] are associates with floodwaters. The major route of [[infection]] by leptospires is probably by transmission through indirect contact with leptospires secreted into the environment. Humans are considered dead end hosts, but sometimes they also act as carriers. Mammalian species (e.g. rodents, insectivores, dogs, pigs and cattle) act as the main carriers of the disease.<ref name="pmid20186328">{{cite journal| author=Ganoza CA, Matthias MA, Saito M, Cespedes M, Gotuzzo E, Vinetz JM| title=Asymptomatic renal colonization of humans in the peruvian Amazon by Leptospira. | journal=PLoS Negl Trop Dis | year= 2010 | volume= 4 | issue= 2 | pages= e612 | pmid=20186328 | doi=10.1371/journal.pntd.0000612 | pmc=2826405 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20186328  }} </ref>
Leptospires are excreted in urine into the environment, where they can survive for several months, depending on favourable environmental conditions such as humid and temperate areas. The [[pathogen]] may also be excreted in the products of abortion in mammalian animal species.<ref name="pmid4081333">{{cite journal| author=Ellis WA, O'Brien JJ, Cassells JA, Neill SD, Hanna J| title=Excretion of Leptospira interrogans serovar hardjo following calving or abortion. | journal=Res Vet Sci | year= 1985 | volume= 39 | issue= 3 | pages= 296-8 | pmid=4081333 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4081333  }} </ref>


<ref name="Budihal2014">{{cite journal|last1=Budihal|first1=Suman Veerappa|title=Leptospirosis Diagnosis: Competancy of Various Laboratory Tests|journal=JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH|year=2014|issn=2249782X|doi=10.7860/JCDR/2014/6593.3950}}</ref><ref name="pmid14902167">{{cite journal| author=BEESON PB, HANKEY DD| title=Leptospiral meningitis. | journal=AMA Arch Intern Med | year= 1952 | volume= 89 | issue= 4 | pages= 575-83 | pmid=14902167 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14902167  }} </ref><ref name="pmid1224630">{{cite journal| author=King SD, Urquhart AE| title=Laboratory investigations on four cases of leptospiral meningitis in Jamaica. | journal=West Indian Med J | year= 1975 | volume= 24 | issue= 4 | pages= 196-201 | pmid=1224630 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1224630  }} </ref><ref name="pmid9071036">{{cite journal| author=Silva MV, Camargo ED, Batista L, Vaz AJ, Ferreira AW, Barbosa PR| title=Application of anti-leptospira ELISA-IgM for the etiologic elucidation of meningitis. | journal=Rev Inst Med Trop Sao Paulo | year= 1996 | volume= 38 | issue= 2 | pages= 153-6 | pmid=9071036 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9071036  }} </ref>
Pathological findings of leptospirosis are due to the development of the following:<ref name="Budihal2014">{{cite journal|last1=Budihal|first1=Suman Veerappa|title=Leptospirosis Diagnosis: Competancy of Various Laboratory Tests|journal=JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH|year=2014|issn=2249782X|doi=10.7860/JCDR/2014/6593.3950}}</ref><ref name="pmid14902167">{{cite journal| author=BEESON PB, HANKEY DD| title=Leptospiral meningitis. | journal=AMA Arch Intern Med | year= 1952 | volume= 89 | issue= 4 | pages= 575-83 | pmid=14902167 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14902167  }} </ref><ref name="pmid1224630">{{cite journal| author=King SD, Urquhart AE| title=Laboratory investigations on four cases of leptospiral meningitis in Jamaica. | journal=West Indian Med J | year= 1975 | volume= 24 | issue= 4 | pages= 196-201 | pmid=1224630 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1224630  }} </ref><ref name="pmid9071036">{{cite journal| author=Silva MV, Camargo ED, Batista L, Vaz AJ, Ferreira AW, Barbosa PR| title=Application of anti-leptospira ELISA-IgM for the etiologic elucidation of meningitis. | journal=Rev Inst Med Trop Sao Paulo | year= 1996 | volume= 38 | issue= 2 | pages= 153-6 | pmid=9071036 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9071036  }} </ref>
* [[Vasculitis]]
* [[Endothelial]] damage
* [[Inflammatory]] infiltrates composed of [[monocytic]] cells, [[plasma cells]], [[histiocytes]], and [[neutrophils]].


===Pathophysiology===
{| border="0"
{| border="1"
|-
|-
!colspan="2"| Type of toxin production depends on the serovar
|align=center| '''Leptospira'''
'''Hemolytic toxins:'''
 
Hemolysins are produced from several serovars such as serovars ballum, hardjo, pomona, and tarassovi which are sphingomyelinases
 
'''Leptospira'''
 
'''⬇'''
'''⬇'''


'''[[Toxin]] production'''
'''[[Toxin]] production'''


'''Type of toxin production depends on the serovar'''
* [[Hemolysin|Hemolysins]] are produced from several serovars such as serovars ballum, hardjo, pomona, and tarassovi which are [[Sphingomyelinase|sphingomyelinases]]
* Protein [[cytotoxins]] are produced by strains of serovars pomona and copenhageni
* [[Glycolipids|Glycolipoprotein]] fraction with [[Cytotoxicity|cytotoxic activity]] produced by serovar copenhageni
'''⬇'''
'''⬇'''


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'''Acute renal injury and [[vascular]] injury to internal organs'''
'''Acute renal injury and [[vascular]] injury to internal organs'''
|}
|}
===Pathology===
 
{| border="2" cellpadding="4" cellspacing="0" style="margin: 1em 1em 1em 0; background: #f9f9f9; border: 1px #aaa solid; border-collapse: collapse;" width="75%"
==Gross Pathology==
!colspan="1" style="background: #4479BA; text-align: center;" | {{fontcolor|#FFF| '''Pathology'''}}
Gross findings of various organ systems are present as:<ref name="pmid13862141">{{cite journal| author=AREAN VM| title=The pathologic anatomy and pathogenesis of fatal human leptospirosis (Weil's disease). | journal=Am J Pathol | year= 1962 | volume= 40 | issue=  | pages= 393-423 | pmid=13862141 | doi= | pmc=1949541 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13862141  }} </ref>
|-
|Pathological findings of leptospirosis are due to the development of the following:
* [[Vasculitis]]
* [[Endothelial]] damage
* [[Inflammatory]] infiltrates composed of moncytic cells, [[plasma cells]], [[histiocytes]], and [[neutrophils]].
|-
!colspan="1" style="background: #4479BA; text-align: center;" | {{fontcolor|#FFF| '''Gross Findings'''}}
|-
|Gross findings of various organ systems are present as:<ref name="pmid13862141">{{cite journal| author=AREAN VM| title=The pathologic anatomy and pathogenesis of fatal human leptospirosis (Weil's disease). | journal=Am J Pathol | year= 1962 | volume= 40 | issue=  | pages= 393-423 | pmid=13862141 | doi= | pmc=1949541 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13862141  }} </ref>
* Extensive [[petechial hemorrhages]] are common.  
* Extensive [[petechial hemorrhages]] are common.  
* Discoloration of organs is seen in severe cases of icteric leptospirosis.
* Discoloration of organs is seen in severe cases of icteric leptospirosis.
|-
 
!colspan="1" style="background: #4479BA; text-align: center;" | {{fontcolor|#FFF| '''Histopathological Findings'''}}
== Microscopic Pathology ==
|-
===Liver===
|'''Liver:'''
* No significant structural destruction is seen<ref name="pmid13862141">{{cite journal| author=AREAN VM| title=The pathologic anatomy and pathogenesis of fatal human leptospirosis (Weil's disease). | journal=Am J Pathol | year= 1962 | volume= 40 | issue=  | pages= 393-423 | pmid=13862141 | doi= | pmc=1949541 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13862141  }} </ref><ref name="pmid4298629">{{cite journal| author=De Brito T, Machado MM, Montans SD, Hoshino S, Freymüller E| title=Liver biopsy in human leptospirosis: a light and electron microscopy study. | journal=Virchows Arch Pathol Anat Physiol Klin Med | year= 1967 | volume= 342 | issue= 1 | pages= 61-9 | pmid=4298629 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4298629  }} </ref>
* No significant structural destruction is seen<ref name="pmid13862141">{{cite journal| author=AREAN VM| title=The pathologic anatomy and pathogenesis of fatal human leptospirosis (Weil's disease). | journal=Am J Pathol | year= 1962 | volume= 40 | issue=  | pages= 393-423 | pmid=13862141 | doi= | pmc=1949541 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13862141  }} </ref><ref name="pmid4298629">{{cite journal| author=De Brito T, Machado MM, Montans SD, Hoshino S, Freymüller E| title=Liver biopsy in human leptospirosis: a light and electron microscopy study. | journal=Virchows Arch Pathol Anat Physiol Klin Med | year= 1967 | volume= 342 | issue= 1 | pages= 61-9 | pmid=4298629 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4298629  }} </ref>
* [[Intrahepatic cholestasis]]  is seen in few cases
* [[Intrahepatic cholestasis]]  is seen in few cases
* [[Hypertrophy (medical)|Hypertrophy]] and [[hyperplasia]] of [[Kupffer cells]]  
* [[Hypertrophy (medical)|Hypertrophy]] and [[hyperplasia]] of [[Kupffer cells]]  
* Erythrophagocytosis
* Erythrophagocytosis
'''Kidney:'''
===Kidney===
* Common histopathological presentation in kidney includes [[interstitial nephritis]] with infiltration of [[neutrophils]] and [[Monocytes|monocytes.]]<ref name="pmid13862141">{{cite journal| author=AREAN VM| title=The pathologic anatomy and pathogenesis of fatal human leptospirosis (Weil's disease). | journal=Am J Pathol | year= 1962 | volume= 40 | issue=  | pages= 393-423 | pmid=13862141 | doi= | pmc=1949541 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13862141  }} </ref>
* Common [[histopathological]] presentation in [[kidney]] includes [[interstitial nephritis]] with infiltration of [[neutrophils]] and [[Monocytes|monocytes.]]<ref name="pmid13862141">{{cite journal| author=AREAN VM| title=The pathologic anatomy and pathogenesis of fatal human leptospirosis (Weil's disease). | journal=Am J Pathol | year= 1962 | volume= 40 | issue=  | pages= 393-423 | pmid=13862141 | doi= | pmc=1949541 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13862141  }} </ref>
* Leptospires are seen in [[renal tubules]].
* Leptospires are seen in [[renal tubules]].
* Electron microscopy findings include:<ref name="pmid14072448">{{cite journal| author=PENNA D, DE BRITO T, PUPO AA, MACHADO MM, AYROZA PA, DE ALMEIDA SS| title=KIDNEY BIOPSY IN HUMAN LEPTOSPIROSIS. | journal=Am J Trop Med Hyg | year= 1963 | volume= 12 | issue=  | pages= 896-901 | pmid=14072448 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14072448  }} </ref><ref name="SitprijaEvans1970">{{cite journal|last1=Sitprija|first1=Visith|last2=Evans|first2=Hilary|title=The kidney in human leptospirosis|journal=The American Journal of Medicine|volume=49|issue=6|year=1970|pages=780–788|issn=00029343|doi=10.1016/S0002-9343(70)80059-6}}</ref>
* Electron microscopy findings include:<ref name="pmid14072448">{{cite journal| author=PENNA D, DE BRITO T, PUPO AA, MACHADO MM, AYROZA PA, DE ALMEIDA SS| title=KIDNEY BIOPSY IN HUMAN LEPTOSPIROSIS. | journal=Am J Trop Med Hyg | year= 1963 | volume= 12 | issue=  | pages= 896-901 | pmid=14072448 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14072448  }} </ref><ref name="SitprijaEvans1970">{{cite journal|last1=Sitprija|first1=Visith|last2=Evans|first2=Hilary|title=The kidney in human leptospirosis|journal=The American Journal of Medicine|volume=49|issue=6|year=1970|pages=780–788|issn=00029343|doi=10.1016/S0002-9343(70)80059-6}}</ref>
Line 80: Line 72:
** Thickened tubular [[basement membrane]]
** Thickened tubular [[basement membrane]]
** Denuded tubular brush borders
** Denuded tubular brush borders
** Mitochondrial depletion in tubular cells
** [[Mitochondrial]] depletion in tubular cells
* Glomerular destruction associated with [[proteinuria]] is seen in few cases.
* [[Glomerular]] destruction associated with [[proteinuria]] is seen in few cases.
'''Heart:'''
===Heart===
 
Leptospirosis is associate with [[interstitial]] [[myocarditis]].<ref name="pmid3446572">{{cite journal| author=De Biase L, De Curtis G, Paparoni S, Sciarra D, Campa PP| title=Fatal leptospiral myocarditis. | journal=G Ital Cardiol | year= 1987 | volume= 17 | issue= 11 | pages= 992-4 | pmid=3446572 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3446572  }} </ref><ref name="BritoMorais2016">{{cite journal|last1=Brito|first1=T. De|last2=Morais|first2=C. F.|last3=Yasuda|first3=P. H.|last4=Lancellotti|first4=Carmen P.|last5=Hoshino-Shimizu|first5=Sumie|last6=Yamashiro|first6=E.|last7=Alves|first7=V. A. Ferreira|title=Cardiovascular involvement in human and experimental leptospirosis: Pathologic findings and immunohistochemical detection of leptospiral antigen|journal=Annals of Tropical Medicine & Parasitology|volume=81|issue=3|year=2016|pages=207–214|issn=0003-4983|doi=10.1080/00034983.1987.11812114}}</ref><ref name="pmid13464040">{{cite journal| author=AREAN VM| title=Leptospiral myocarditis. | journal=Lab Invest | year= 1957 | volume= 6 | issue= 5 | pages= 462-71 | pmid=13464040 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13464040  }} </ref><ref name="pmid871034">{{cite journal| author=Ramachandran S, Perera MV| title=Cardiac and pulmonary involvement in leptospirosis. | journal=Trans R Soc Trop Med Hyg | year= 1977 | volume= 71 | issue= 1 | pages= 56-9 | pmid=871034 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=871034  }} </ref>
Leptospirosis is associate with interstitial [[myocarditis]].<ref name="pmid3446572">{{cite journal| author=De Biase L, De Curtis G, Paparoni S, Sciarra D, Campa PP| title=Fatal leptospiral myocarditis. | journal=G Ital Cardiol | year= 1987 | volume= 17 | issue= 11 | pages= 992-4 | pmid=3446572 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3446572  }} </ref><ref name="BritoMorais2016">{{cite journal|last1=Brito|first1=T. De|last2=Morais|first2=C. F.|last3=Yasuda|first3=P. H.|last4=Lancellotti|first4=Carmen P.|last5=Hoshino-Shimizu|first5=Sumie|last6=Yamashiro|first6=E.|last7=Alves|first7=V. A. Ferreira|title=Cardiovascular involvement in human and experimental leptospirosis: Pathologic findings and immunohistochemical detection of leptospiral antigen|journal=Annals of Tropical Medicine & Parasitology|volume=81|issue=3|year=2016|pages=207–214|issn=0003-4983|doi=10.1080/00034983.1987.11812114}}</ref><ref name="pmid13464040">{{cite journal| author=AREAN VM| title=Leptospiral myocarditis. | journal=Lab Invest | year= 1957 | volume= 6 | issue= 5 | pages= 462-71 | pmid=13464040 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13464040  }} </ref><ref name="pmid871034">{{cite journal| author=Ramachandran S, Perera MV| title=Cardiac and pulmonary involvement in leptospirosis. | journal=Trans R Soc Trop Med Hyg | year= 1977 | volume= 71 | issue= 1 | pages= 56-9 | pmid=871034 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=871034  }} </ref>
* [[Cellular infiltration]] predominantly with [[lymphocytes]] and [[plasma cells]].
* Cellular infiltration predominantly with [[lymphocytes]] and [[plasma cells]].
* [[Petechial hemorrhages]] ([[epicardial]] hemorrhages are common)  
* [[Petechial hemorrhages]] (epicardial hemorrhages are common)  
* Epicardial infiltration of [[mononuclear cells]].
* Epicardial infilteration of [[mononuclear cells]].
* [[Pericardial effusion]]
* [[Pericardial effusion]]
* coronary arteritis
* [[Coronary]] [[arteritis]]
'''Lungs:'''
===Lungs===
Common [[pulmonary]] presentation in leptospirosis are [[pulmonary congestion]] and [[hemorrhage]].<ref name="pmid13862141">{{cite journal| author=AREAN VM| title=The pathologic anatomy and pathogenesis of fatal human leptospirosis (Weil's disease). | journal=Am J Pathol | year= 1962 | volume= 40 | issue=  | pages= 393-423 | pmid=13862141 | doi= | pmc=1949541 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13862141  }} </ref><ref name="pmid871034">{{cite journal| author=Ramachandran S, Perera MV| title=Cardiac and pulmonary involvement in leptospirosis. | journal=Trans R Soc Trop Med Hyg | year= 1977 | volume= 71 | issue= 1 | pages= 56-9 | pmid=871034 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=871034  }} </ref><ref name="pmid9080878">{{cite journal| author=Nicodemo AC, Duarte MI, Alves VA, Takakura CF, Santos RT, Nicodemo EL| title=Lung lesions in human leptospirosis: microscopic, immunohistochemical, and ultrastructural features related to thrombocytopenia. | journal=Am J Trop Med Hyg | year= 1997 | volume= 56 | issue= 2 | pages= 181-7 | pmid=9080878 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9080878  }} </ref><ref name="pmid6790049">{{cite journal| author=Zaltzman M, Kallenbach JM, Goss GD, Lewis M, Zwi S, Gear JH| title=Adult respiratory distress syndrome in Leptospira canicola infection. | journal=Br Med J (Clin Res Ed) | year= 1981 | volume= 283 | issue= 6290 | pages= 519-20 | pmid=6790049 | doi= | pmc=1507945 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6790049  }} </ref>
* [[Alveolar]] infiltration by [[monocytes]] and [[neutrophils]].
* Hyaline membrane formation.
* Leptospires are seen within the [[endothelial cells]] in interalveolar septa, and also attached to [[capillary]] [[endothelial cells]].
===Skeletal muscle===
* Focal [[necrosis]] of [[muscle]] fibers with infiltration of [[histiocytes]], [[neutrophils]], and [[plasma cells]].
===Brain===
* [[Perivascular cell|Perivascular]] cuffing is seen.


Common pulmonary presentation in leptospirosis are [[pulmonary congestion]] and [[hemorrhage]].<ref name="pmid13862141">{{cite journal| author=AREAN VM| title=The pathologic anatomy and pathogenesis of fatal human leptospirosis (Weil's disease). | journal=Am J Pathol | year= 1962 | volume= 40 | issue=  | pages= 393-423 | pmid=13862141 | doi= | pmc=1949541 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13862141  }} </ref><ref name="pmid871034">{{cite journal| author=Ramachandran S, Perera MV| title=Cardiac and pulmonary involvement in leptospirosis. | journal=Trans R Soc Trop Med Hyg | year= 1977 | volume= 71 | issue= 1 | pages= 56-9 | pmid=871034 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=871034  }} </ref><ref name="pmid9080878">{{cite journal| author=Nicodemo AC, Duarte MI, Alves VA, Takakura CF, Santos RT, Nicodemo EL| title=Lung lesions in human leptospirosis: microscopic, immunohistochemical, and ultrastructural features related to thrombocytopenia. | journal=Am J Trop Med Hyg | year= 1997 | volume= 56 | issue= 2 | pages= 181-7 | pmid=9080878 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9080878  }} </ref><ref name="pmid6790049">{{cite journal| author=Zaltzman M, Kallenbach JM, Goss GD, Lewis M, Zwi S, Gear JH| title=Adult respiratory distress syndrome in Leptospira canicola infection. | journal=Br Med J (Clin Res Ed) | year= 1981 | volume= 283 | issue= 6290 | pages= 519-20 | pmid=6790049 | doi= | pmc=1507945 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6790049  }} </ref>
* Alveolar infiltration by [[monocytes]] and [[neutrophils]].
* Hyaline membrane formation.
* Leptospires are seen within the [[endothelial cells]] in interalveolar septa, and also attached to capillary endothelial cells.
'''Skeletal muscle:'''
* Focal [[necrosis]] of muscle fibers with infiltration of [[histiocytes]], [[neutrophils]], and [[plasma cells]].
'''Brain:'''
* Perivascular cuffing is seen.
|}
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
[[Category:Emergency mdicine]]
[[Category:Disease]]
[[Category:Up-To-Date]]
[[Category:Infectious disease]]
[[Category:Pulmonology]]
[[Category:Gastroenterology]]
[[Category:Otolaryngology]]
[[Category:Neurology]]

Latest revision as of 22:29, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Venkata Sivakrishna Kumar Pulivarthi M.B.B.S [2]

Overview

Leptospires shed in the urine of animals to the environment from where humans are infected by incidental hosts. In Carriers these bacteria harbor in the renal tubules and can persist in soil or surface water and then transmits to human hosts via mucous membranes or abraded skin.[1][2] Pathogen transmit through various mechanisms such as broken skin, mucus membranes and the conjunctivae, exposure to contaminated water are at risk of contracting leptospirosis.[3]

Pathogenesis

The disease leptospirosis involves a spectrum of symptoms ranging from subclinical infection to a severe syndrome of multiorgan infection with high mortality and Weil’s disease represents only the most severe presentation. Severe leptospirosis is frequently caused by serovars of the icterohaemorrhagiae serogroup. The presentation of leptospirosis is biphasic, with the acute or septicemic phase lasting about a week, followed by the immune phase, characterized by antibody production and excretion of leptospires in the urine.[4]

Reservoirs

The major reservoir for leptospirosis is rat and small rodents that appear to harbour more virulent strains of the disease.[5]

Carriers

Domestic animals such as dogs,cattle and pigs acts as potential carriers that increases the risk of leptospirosis in humans. These carriers are generally asymptomatic.[6][7]

Modes of transmission

  1. Direct contact with urine or tissue of infected animal: Through skin abrasions and intact mucus membrane
  2. Indirect contact: Broken skin with infected soil, water or vegetation, Through ingestion of contaminated food and water
  3. Droplet infection: Inhalation of droplets of infected urine

Infection can occurs either by direct contact with the carrier’s urine or through indirect transmission via urine-contaminated environment. Infection due to direct transmission through direct oral intake of contaminated drinking water or food is very rare.[8] Pathogenic leptospires live in the renal system and the genital tracts of domestic animals which act as sites of persistence.[9][10] Bacteria shed from the infected animals such as rodents and domesticat animals through urine. These animals may not show signs of disease but humans shows signs of illness after contact with infected urine, or through contact with water, soil or food that has been contaminated and the outbreaks are associates with floodwaters. The major route of infection by leptospires is probably by transmission through indirect contact with leptospires secreted into the environment. Humans are considered dead end hosts, but sometimes they also act as carriers. Mammalian species (e.g. rodents, insectivores, dogs, pigs and cattle) act as the main carriers of the disease.[11] Leptospires are excreted in urine into the environment, where they can survive for several months, depending on favourable environmental conditions such as humid and temperate areas. The pathogen may also be excreted in the products of abortion in mammalian animal species.[9]

Pathological findings of leptospirosis are due to the development of the following:[12][13][14][15]

Leptospira

⬇

Toxin production

Type of toxin production depends on the serovar

⬇

Damage to small blood vessels

⬇

Vasculitis

⬇

• Direct cytotoxic injury or Immunological injury
 • Fluid extavasation into the interstitial compartment due to vasculitis

⬇

Acute renal injury and vascular injury to internal organs

Gross Pathology

Gross findings of various organ systems are present as:[16]

  • Extensive petechial hemorrhages are common.
  • Discoloration of organs is seen in severe cases of icteric leptospirosis.

Microscopic Pathology

Liver

Kidney

Heart

Leptospirosis is associate with interstitial myocarditis.[20][21][22][23]

Lungs

Common pulmonary presentation in leptospirosis are pulmonary congestion and hemorrhage.[16][23][24][25]

Skeletal muscle

Brain

References

  1. ↑ BABUDIERI B (1958). "Animal reservoirs of leptospires". Ann N Y Acad Sci. 70 (3): 393–413. PMID 13559904.
  2. ↑ Forbes, A. E.; Zochowski, W. J.; Dubrey, S. W.; Sivaprakasam, V. (2012). "Leptospirosis and Weil's disease in the UK". QJM. 105 (12): 1151–1162. doi:10.1093/qjmed/hcs145. ISSN 1460-2725.
  3. ↑ Forbes AE, Zochowski WJ, Dubrey SW, Sivaprakasam V (2012). "Leptospirosis and Weil's disease in the UK". QJM. 105 (12): 1151–62. doi:10.1093/qjmed/hcs145. PMID 22843698.
  4. ↑ Levett, P. N. (2001). "Leptospirosis". Clinical Microbiology Reviews. 14 (2): 296–326. doi:10.1128/CMR.14.2.296-326.2001. ISSN 0893-8512.
  5. ↑ Picardeau, M. (2013). "Diagnosis and epidemiology of leptospirosis". Médecine et Maladies Infectieuses. 43 (1): 1–9. doi:10.1016/j.medmal.2012.11.005. ISSN 0399-077X.
  6. ↑ Gaudie CM, Featherstone CA, Phillips WS, McNaught R, Rhodes PM, Errington J; et al. (2008). "Human Leptospira interrogans serogroup icterohaemorrhagiae infection (Weil's disease) acquired from pet rats". Vet Rec. 163 (20): 599–601. PMID 19011247.
  7. ↑ Strugnell BW, Featherstone C, Gent M, Lister P, Evans G, Okereke E; et al. (2009). "Weil's disease associated with the adoption of a feral rat". Vet Rec. 164 (6): 186. PMID 19202179.
  8. ↑ Cacciapuoti B, Ciceroni L, Maffei C, Di Stanislao F, Strusi P, Calegari L; et al. (1987). "A waterborne outbreak of leptospirosis". Am J Epidemiol. 126 (3): 535–45. PMID 3618584.
  9. ↑ 9.0 9.1 Ellis WA, O'Brien JJ, Cassells JA, Neill SD, Hanna J (1985). "Excretion of Leptospira interrogans serovar hardjo following calving or abortion". Res Vet Sci. 39 (3): 296–8. PMID 4081333.
  10. ↑ Ellis WA, McParland PJ, Bryson DG, Thiermann AB, Montgomery J (1986). "Isolation of leptospires from the genital tract and kidneys of aborted sows". Vet Rec. 118 (11): 294–5. PMID 3705357.
  11. ↑ Ganoza CA, Matthias MA, Saito M, Cespedes M, Gotuzzo E, Vinetz JM (2010). "Asymptomatic renal colonization of humans in the peruvian Amazon by Leptospira". PLoS Negl Trop Dis. 4 (2): e612. doi:10.1371/journal.pntd.0000612. PMC 2826405. PMID 20186328.
  12. ↑ Budihal, Suman Veerappa (2014). "Leptospirosis Diagnosis: Competancy of Various Laboratory Tests". JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH. doi:10.7860/JCDR/2014/6593.3950. ISSN 2249-782X.
  13. ↑ BEESON PB, HANKEY DD (1952). "Leptospiral meningitis". AMA Arch Intern Med. 89 (4): 575–83. PMID 14902167.
  14. ↑ King SD, Urquhart AE (1975). "Laboratory investigations on four cases of leptospiral meningitis in Jamaica". West Indian Med J. 24 (4): 196–201. PMID 1224630.
  15. ↑ Silva MV, Camargo ED, Batista L, Vaz AJ, Ferreira AW, Barbosa PR (1996). "Application of anti-leptospira ELISA-IgM for the etiologic elucidation of meningitis". Rev Inst Med Trop Sao Paulo. 38 (2): 153–6. PMID 9071036.
  16. ↑ 16.0 16.1 16.2 16.3 AREAN VM (1962). "The pathologic anatomy and pathogenesis of fatal human leptospirosis (Weil's disease)". Am J Pathol. 40: 393–423. PMC 1949541. PMID 13862141.
  17. ↑ De Brito T, Machado MM, Montans SD, Hoshino S, Freymüller E (1967). "Liver biopsy in human leptospirosis: a light and electron microscopy study". Virchows Arch Pathol Anat Physiol Klin Med. 342 (1): 61–9. PMID 4298629.
  18. ↑ PENNA D, DE BRITO T, PUPO AA, MACHADO MM, AYROZA PA, DE ALMEIDA SS (1963). "KIDNEY BIOPSY IN HUMAN LEPTOSPIROSIS". Am J Trop Med Hyg. 12: 896–901. PMID 14072448.
  19. ↑ Sitprija, Visith; Evans, Hilary (1970). "The kidney in human leptospirosis". The American Journal of Medicine. 49 (6): 780–788. doi:10.1016/S0002-9343(70)80059-6. ISSN 0002-9343.
  20. ↑ De Biase L, De Curtis G, Paparoni S, Sciarra D, Campa PP (1987). "Fatal leptospiral myocarditis". G Ital Cardiol. 17 (11): 992–4. PMID 3446572.
  21. ↑ Brito, T. De; Morais, C. F.; Yasuda, P. H.; Lancellotti, Carmen P.; Hoshino-Shimizu, Sumie; Yamashiro, E.; Alves, V. A. Ferreira (2016). "Cardiovascular involvement in human and experimental leptospirosis: Pathologic findings and immunohistochemical detection of leptospiral antigen". Annals of Tropical Medicine & Parasitology. 81 (3): 207–214. doi:10.1080/00034983.1987.11812114. ISSN 0003-4983.
  22. ↑ AREAN VM (1957). "Leptospiral myocarditis". Lab Invest. 6 (5): 462–71. PMID 13464040.
  23. ↑ 23.0 23.1 Ramachandran S, Perera MV (1977). "Cardiac and pulmonary involvement in leptospirosis". Trans R Soc Trop Med Hyg. 71 (1): 56–9. PMID 871034.
  24. ↑ Nicodemo AC, Duarte MI, Alves VA, Takakura CF, Santos RT, Nicodemo EL (1997). "Lung lesions in human leptospirosis: microscopic, immunohistochemical, and ultrastructural features related to thrombocytopenia". Am J Trop Med Hyg. 56 (2): 181–7. PMID 9080878.
  25. ↑ Zaltzman M, Kallenbach JM, Goss GD, Lewis M, Zwi S, Gear JH (1981). "Adult respiratory distress syndrome in Leptospira canicola infection". Br Med J (Clin Res Ed). 283 (6290): 519–20. PMC 1507945. PMID 6790049.
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