Relapsing fever pathophysiology: Difference between revisions

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keywords: VMP:Variable membrane proteins
keywords: VMP:Variable membrane proteins
==Overview==
==Overview==
[[Borrelia]] is usually transmitted via the [[tick bite]] or [[body louse]] to the human host. After entering the [[bloodstream]], [[spirochetes]] replicate [[Extracellular|extracellularly]] and remain predominantly in the [[plasma]] space. Patients generally remain [[asymptomatic]] until high-level [[spirochetemia]] (104-108 organisms m!) develops, at which time symptoms begin abruptly. Organisms are cleared predominantly by opsonizing [[antibodies]] with the resolution of symptoms ( [[afebrile]] period), followed several days or weeks later by the reemergence of a new [[antigenic]] strain, high-level [[spirochetemia]], and recurrence of symptoms. There are multiple [[genes]] in the [[spirochete]] encoding [[variable]] [[membrane]] [[proteins]]( [[VMPs]]). These '''VMPs''' determine the antigenic serotype of the organism. At any given time, each [[spirochete]] has VMP genes that are [[expressed]] and others that are [[silent]]. An [[Antigenic variation|antigenic switch]] occurs when a given [[VMP]] gene transposes from silent to an expressed [[locus]]. This cyclical process of initially effective [[immune response]] followed by [[antigenic variation]] and [[immunologic]] escape is responsible for the relapsing nature of this illness.
[[Borrelia]] is usually transmitted via the [[tick bite]] or [[body louse]] to the human host. After entering the [[bloodstream]], [[spirochetes]] replicate [[Extracellular|extracellularly]] and remain predominantly in the [[plasma]] space. Patients generally remain [[asymptomatic]] until high-level [[spirochetemia]] develops, at which time [[symptoms]] begin abruptly. Organisms are cleared predominantly by opsonizing [[antibodies]] with the resolution of [[symptoms]] ( [[afebrile]] period), followed several days or weeks later by the reemergence of a new [[antigenic]] strain, high-level [[spirochetemia]], and recurrence of [[symptoms]]. There are multiple [[genes]] in the [[spirochete]] encoding [[variable]] [[membrane]] [[proteins]]( [[VMPs]]). These '''VMPs''' determine the [[antigenic]] [[serotype]] of the [[organism]]. At any given time, each [[spirochete]] has VMP [[genes]] that are [[expressed]] and others that are [[silent]]. An [[Antigenic variation|antigenic switch]] occurs when a given [[VMP]] gene transposes from silent to an expressed [[locus]]. This cyclical process of initially effective [[immune response]] followed by [[antigenic variation]] and [[immunologic]] escape is responsible for the relapsing nature of this illness.


==Pathophysiology==
==Pathophysiology==
===Cyclical process===
*[[Borrelia]] is usually transmitted via the [[tick bite]] or [[body louse]] to the human host.
*[[Borrelia]] is usually transmitted via the [[tick bite]] or [[body louse]] to the human host.
===Cyclical process===
*[[Borrelia]] is able to induce cycles of disease by varying antigen expression and by displaying new [[Outer membrane|outer-surface proteins]](VMPs) during the disease course([[antigenic variation]]). The antigenic variation contributes to the recurring nature of [[relapsing fever]].There are multiple [[genes]] in the [[spirochete]] encoding [[variable]] [[membrane]] [[proteins]]( [[VMPs]]). These '''VMPs''' determine the antigenic serotype of the organism. At any given time, each [[spirochete]] has VMP genes that are [[expressed]] and others that are [[silent]]. An [[Antigenic variation|antigenic switch]] occurs when a given [[VMP]] gene transposes from silent to an expressed [[locus]]. This cyclical process of initially effective [[immune response]] followed by [[antigenic variation]] and [[immunologic]] escape is responsible for the relapsing nature of this illness.
Borrelia is able to induce cycles of disease by varying antigen expression and by displaying new outer-surface proteins(VMPs) during the disease course(antigenic variation). The antigenic variation contributes to the recurring nature of relapsing fever.There are multiple [[genes]] in the [[spirochete]] encoding [[variable]] [[membrane]] [[proteins]]( [[VMPs]]). These '''VMPs''' determine the antigenic serotype of the organism. At any given time, each [[spirochete]] has VMP genes that are [[expressed]] and others that are [[silent]]. An [[Antigenic variation|antigenic switch]] occurs when a given [[VMP]] gene transposes from silent to an expressed [[locus]]. This cyclical process of initially effective [[immune response]] followed by [[antigenic variation]] and [[immunologic]] escape is responsible for the relapsing nature of this illness.


===Incubation period===
===Incubation period===
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[[Symptomatic]] period= Length of illness = time from symptom onset to resolution of symptoms
[[Symptomatic]] period= Length of illness = time from symptom onset to resolution of symptoms
* 3 days, range 2 to 7 days
* 3 days, range 2 to 7 days
*During episodes of [[spirochetemia]] and replicate [[extracellularly]] and remain predominantly the [[plasma]] space. [[Borrelia]] invades the [[endothelium]]. After multiplying in the [[endothelial cells]], the [[bacteria]] are released into the [[bloodstream]] and patients develop symptoms that include [[fever]]. However,the [[organisms]] may invade the brain, eye, inner ear, heart, liver. Splenic [[abscesses]] and infarcts, and hemorrhages within the central nervous system, a perivascular histiocytic interstitial [[myocarditis]], conduction defects, [[arrhythmias]], and [[myocardial]] failure, [[splenic rupture]] with massive hemorrhage, [[cerebral hemorrhage]], and [[hepatic failure]] are seen in LBRF which can result in sudden death.Hepatitis with patchy [[hemorrhages]] and [[necrosis]], [[meningitis]], and [[perisplenitis]], thrombi in small [[vessels]] also are found. [[Thrombi]] are occasionally found occluding [[small vessel]]s.<ref name="pmid30869050">{{cite journal |vauthors=Warrell DA |title=Louse-borne relapsing fever (Borrelia recurrentis infection) |journal=Epidemiol. Infect. |volume=147 |issue= |pages=e106 |date=January 2019 |pmid=30869050 |pmc=6518520 |doi=10.1017/S0950268819000116 |url=}}</ref>CNS involvement is more common in TBRF than LBRF, however eschars, ARDS, cranial nerve palsies, focal neurologic deficits, uveitis, iritis or iridocyclitis, splenic rupture and myocarditis may be seen in both TBRF and LBRF.<ref name="pmid18646588">{{cite journal |vauthors=Blevins SM, Greenfield RA, Bronze MS |title=Blood smear analysis in babesiosis, ehrlichiosis, relapsing fever, malaria, and Chagas disease |journal=Cleve Clin J Med |volume=75 |issue=7 |pages=521–30 |date=July 2008 |pmid=18646588 |doi=10.3949/ccjm.75.7.521 |url=}}</ref><ref name="pmid18755384">{{cite journal |vauthors=Dworkin MS, Schwan TG, Anderson DE, Borchardt SM |title=Tick-borne relapsing fever |journal=Infect. Dis. Clin. North Am. |volume=22 |issue=3 |pages=449–68, viii |date=September 2008 |pmid=18755384 |pmc=3725823 |doi=10.1016/j.idc.2008.03.006 |url=}}</ref>Most information on the pathophysiologic aspects of fatal cases comes from autopsy data of louse-borne disease in humans or experimental animals.<ref name="pmid18755384">{{cite journal |vauthors=Dworkin MS, Schwan TG, Anderson DE, Borchardt SM |title=Tick-borne relapsing fever |journal=Infect. Dis. Clin. North Am. |volume=22 |issue=3 |pages=449–68, viii |date=September 2008 |pmid=18755384 |pmc=3725823 |doi=10.1016/j.idc.2008.03.006 |url=}}</ref>
*During episodes of [[spirochetemia]] and replicate [[extracellularly]] and remain predominantly the [[plasma]] space. [[Borrelia]] invades the [[endothelium]]. After multiplying in the [[endothelial cells]], the [[bacteria]] are released into the [[bloodstream]] and patients develop symptoms that include [[fever]]. However,the [[organisms]] may invade the brain, eye, inner ear, heart, liver. Splenic [[abscesses]] and infarcts, and hemorrhages within the central nervous system, a perivascular histiocytic interstitial [[myocarditis]], conduction defects, [[arrhythmias]], and [[myocardial]] failure, [[splenic rupture]] with massive hemorrhage, [[cerebral hemorrhage]], and [[hepatic failure]] are seen in LBRF which can result in sudden death.Hepatitis with patchy [[hemorrhages]] and [[necrosis]], [[meningitis]], and [[perisplenitis]], thrombi in small [[vessels]] also are found. [[Thrombi]] are occasionally found occluding [[small vessel]]s.<ref name="pmid30869050">{{cite journal |vauthors=Warrell DA |title=Louse-borne relapsing fever (Borrelia recurrentis infection) |journal=Epidemiol. Infect. |volume=147 |issue= |pages=e106 |date=January 2019 |pmid=30869050 |pmc=6518520 |doi=10.1017/S0950268819000116 |url=}}</ref>[[CNS]] involvement is more common in [[Tick-borne relapsing fever|TBRF]] than [[Louse-borne relapsing fever|LBRF]], however [[eschar|eschars]], [[ARDS]], [[cranial nerve palsies]], focal neurologic deficits, [[uveitis]], [[iritis]] or [[iridocyclitis]], [[splenic rupture]] and [[myocarditis]] may be seen in both [[Tick-borne relapsing fever|TBRF]] and [[Louse-borne relapsing fever|LBRF]].<ref name="pmid18646588">{{cite journal |vauthors=Blevins SM, Greenfield RA, Bronze MS |title=Blood smear analysis in babesiosis, ehrlichiosis, relapsing fever, malaria, and Chagas disease |journal=Cleve Clin J Med |volume=75 |issue=7 |pages=521–30 |date=July 2008 |pmid=18646588 |doi=10.3949/ccjm.75.7.521 |url=}}</ref><ref name="pmid18755384">{{cite journal |vauthors=Dworkin MS, Schwan TG, Anderson DE, Borchardt SM |title=Tick-borne relapsing fever |journal=Infect. Dis. Clin. North Am. |volume=22 |issue=3 |pages=449–68, viii |date=September 2008 |pmid=18755384 |pmc=3725823 |doi=10.1016/j.idc.2008.03.006 |url=}}</ref>Most information on the pathophysiologic aspects of fatal cases comes from autopsy data of louse-borne disease in humans or experimental animals.<ref name="pmid18755384">{{cite journal |vauthors=Dworkin MS, Schwan TG, Anderson DE, Borchardt SM |title=Tick-borne relapsing fever |journal=Infect. Dis. Clin. North Am. |volume=22 |issue=3 |pages=449–68, viii |date=September 2008 |pmid=18755384 |pmc=3725823 |doi=10.1016/j.idc.2008.03.006 |url=}}</ref>
[[File:Pathophysiology LBRF.jpg|CNS, Eye involvement in LBRF]]
[[File:Pathophysiology LBRF.jpg|CNS, Eye involvement in LBRF]]



Latest revision as of 21:49, 26 September 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Roghayeh Marandi keywords: VMP:Variable membrane proteins

Overview

Borrelia is usually transmitted via the tick bite or body louse to the human host. After entering the bloodstream, spirochetes replicate extracellularly and remain predominantly in the plasma space. Patients generally remain asymptomatic until high-level spirochetemia develops, at which time symptoms begin abruptly. Organisms are cleared predominantly by opsonizing antibodies with the resolution of symptoms ( afebrile period), followed several days or weeks later by the reemergence of a new antigenic strain, high-level spirochetemia, and recurrence of symptoms. There are multiple genes in the spirochete encoding variable membrane proteins( VMPs). These VMPs determine the antigenic serotype of the organism. At any given time, each spirochete has VMP genes that are expressed and others that are silent. An antigenic switch occurs when a given VMP gene transposes from silent to an expressed locus. This cyclical process of initially effective immune response followed by antigenic variation and immunologic escape is responsible for the relapsing nature of this illness.

Pathophysiology

Cyclical process

Incubation period

Incubation period = time from tick bite to illness

  • 7 days, range 2 to 18 days

Symptomatic period

Symptomatic period= Length of illness = time from symptom onset to resolution of symptoms

CNS, Eye involvement in LBRF

Afebrile period

Afebrile period= Length of time before reoccurrence = time from the resolution of symptoms to reoccurrence of symptoms

  • 7 days, range 4 to 14 days
  • Organisms are cleared predominantly by opsonizing antibodies with the resolution of symptoms ( afebrile period), followed several days or weeks later by the reemergence of a new antigenic strain, high-level spirochetemia, when high-level spirochetemia (104-108 organisms m!) develops, at which time symptoms begin abruptly.

Crisis

  • Most cases eventually resolve spontaneously. Occasionally, the crisis occurs after the resolution. During the crisis, patients may develop cerebral edema with seizures, cardiac failure, or death. This stage may result in death in up to 10% of patients.

Immunity

  • Specific serotypes can recur within an individual. Infection with a given strain of Borrelia may cause partial protection against subsequent infection by the same strain. In some highly endemic areas, relapsing fever is more severe in newcomers than natives.

Genetics

The development of the cyclical process is the result of antigenic variation and subsequent immunologic escape:

References

  1. Warrell DA (January 2019). "Louse-borne relapsing fever (Borrelia recurrentis infection)". Epidemiol. Infect. 147: e106. doi:10.1017/S0950268819000116. PMC 6518520 Check |pmc= value (help). PMID 30869050.
  2. Blevins SM, Greenfield RA, Bronze MS (July 2008). "Blood smear analysis in babesiosis, ehrlichiosis, relapsing fever, malaria, and Chagas disease". Cleve Clin J Med. 75 (7): 521–30. doi:10.3949/ccjm.75.7.521. PMID 18646588.
  3. 3.0 3.1 Dworkin MS, Schwan TG, Anderson DE, Borchardt SM (September 2008). "Tick-borne relapsing fever". Infect. Dis. Clin. North Am. 22 (3): 449–68, viii. doi:10.1016/j.idc.2008.03.006. PMC 3725823. PMID 18755384.