Interaction Between Interaction Between SchistosomiasisSchistosomiasis and HCVand HCV

By:By:

Gamal EsmatGamal EsmatPROF.OF HEPATOLOGY&TROPICAL MEDICINEPROF.OF HEPATOLOGY&TROPICAL MEDICINE

CAIRO UNIVERSITYCAIRO UNIVERSITY--EGYPTEGYPT

PRESIDENT OF IASLPRESIDENT OF IASL(INTERN. ASSOC.FOR THE STUDY OF THE LIVER(INTERN. ASSOC.FOR THE STUDY OF THE LIVER))

Prof. Gamal Esmat

Prof. Gamal Esmat

EpidemiologyEpidemiology

Effect of Combined infection Effect of Combined infection

–– ImmunopathogenesisImmunopathogenesis

–– SeveritySeverity

–– SVRSVR

Prof. Gamal Esmat

Prof. Gamal Esmat

Prof. Gamal Esmat

♦Trematode parasitic infection

♦ Intermediate host: water snails

♦Debilitating disease, severity depends on “worm load”

Theodor Bilharz (1825-1862) first described the trematode working at Kasr El Ainy hospital in Cairo

in 1851

Schistosomiasis

Prof. Gamal Esmat

♦ Snail habitat: irrigation canals, lakes, ponds

♦ Humans get infected through skin contact with water

♦ Humans excrete schistosomal eggs in urine or stool into water, keep-up life cycle of parasites

Life cycle of schistosomiasis

Prof. Gamal Esmat

Prof. Gamal Esmat

Prof. Gamal Esmat

(El(El--MenezaMeneza et al., 1989).et al., 1989).

Hepatic fibrosis is the major Hepatic fibrosis is the major

clinical sequel of the infection with clinical sequel of the infection with

the the SchistosomaSchistosoma mansoni.mansoni.

Prof. Gamal Esmat

Hematemesis and Hematemesis and melenamelena are the most are the most common clinical presentation of hepatic common clinical presentation of hepatic SchistosomisisSchistosomisis..Abdominal pain is usually caused by Abdominal pain is usually caused by HepatosplenomegalyHepatosplenomegaly..JuandiceJuandice and manifestations of LCF are and manifestations of LCF are rare clinical presentation.rare clinical presentation.

Prof. Gamal Esmat

HpatitisHpatitis C Virus (HCV)C Virus (HCV)

Prof. Gamal Esmat

Prof. Gamal Esmat

The association of The association of hepatosplenichepatosplenicschistosomiasisschistosomiasis and hepatitis C is very and hepatitis C is very common especially in countries with high common especially in countries with high transmission of both infections e.g., Egypt, transmission of both infections e.g., Egypt, as well as in other endemic areas as as well as in other endemic areas as Brazil. Brazil.

Prof. Gamal Esmat

* age-adjusted prevalence, population between 10 and 50SUDAN

EGYPT

Upper Egypt19.4%

(95% CI: 17.2-21.6)

Middle Egypt26.5%

(95% CI: 23.7-29.4)

Alexandria 5.9% (95% CI: 4.2-7.7)

Lower Egypt28.4%

(95% CI: 27.1-29.2)

Cairo8.2% (95% CI: 6.7-9.8)

LIBYA Red

Sea

Geographic HCV Geographic HCV Prevalence* Prevalence*

Prof. Gamal Esmat

hepatitis C infection in Egypthepatitis C infection in Egypt

Approximately Approximately 90%90% of Egyptian of Egyptian isolates belong to a single isolates belong to a single subtype, subtype, 4a.4a. (Ray et al., 2000, (Ray et al., 2000, Kamal et al., 2000).Kamal et al., 2000).Furthermore, HCV is Furthermore, HCV is less less prevalent in countries prevalent in countries neighbouring Egyptneighbouring Egypt having having similar socio medical conditions similar socio medical conditions and similar strains (WHO 1997).and similar strains (WHO 1997).

One genotype

Higher prevalence than surroundings

Prof. Gamal Esmat

ParenteralParenteral antischistosomalantischistosomal treatment treatment (PAT) programs are believed to have (PAT) programs are believed to have infectedinfected a large proportion of the exposed a large proportion of the exposed population with HCV from 1950s until the population with HCV from 1950s until the early 1980s (early 1980s (NafehNafeh et al., 2000 & et al., 2000 & RaoRao et et al., 2002).al., 2002).

Large reservoir

Prof. Gamal Esmat

The role of parenteral The role of parenteral antischistosomalantischistosomal therapy in the spread of therapy in the spread of hepatitis C virus in Egypt hepatitis C virus in Egypt

(Frank C et al., 2000; Lancet)(Frank C et al., 2000; Lancet)

The risk factor for HCV transmission that The risk factor for HCV transmission that

specifically sets Egypt apart from other specifically sets Egypt apart from other

countries is a personal history of countries is a personal history of parenteral parenteral

antischistosomalantischistosomal therapy (PAT). therapy (PAT).

A review of the Egyptian PAT massA review of the Egyptian PAT mass--

treatment campaigns, discontinued only in treatment campaigns, discontinued only in

the 1980s, show a very high potential for the 1980s, show a very high potential for

transmission of bloodtransmission of blood--borne pathogens. borne pathogens. Prof. Gamal Esmat

This problem is not prominent in other This problem is not prominent in other countries endemic for countries endemic for schistosmiasisschistosmiasisprobably because control efforts were less probably because control efforts were less population intensive and geographically population intensive and geographically extensive.extensive.

Prof. Gamal Esmat

EpidemiologyEpidemiology

Effect of Combined infectionEffect of Combined infection

–– ImmunopathogenesisImmunopathogenesis

–– SeveritySeverity

–– SVRSVR

Prof. Gamal Esmat

ImmunopathogenesisImmunopathogenesis of of Combined InfectionCombined Infection

Dual infection of schistosomiasis and HCV Dual infection of schistosomiasis and HCV display display significant influence on host significant influence on host immune reactionsimmune reactions including cytokine shift including cytokine shift pattern alteration, pattern alteration, cytotoxiccytotoxic T lymphocytes T lymphocytes response and other impaired immunologic response and other impaired immunologic functions with diminished capacity to clear functions with diminished capacity to clear the virus (Elthe virus (El--KadyKady et al., 2004).et al., 2004).

Prof. Gamal Esmat

THoIL-2IFN-γIL-4IL-5IL-10

Th2IL-4IL-5IL-10

+++

Viral clearance

IL-2IFN-γ

Th1+

++

Immunopathogenesisof

Combined infectionProf. Gamal Esmat

ImmunopathogenesisImmunopathogenesis of of Combined InfectionCombined Infection

Schistosomiasis appears to Schistosomiasis appears to induce induce Th2 cytokineTh2 cytokine profile, with profile, with ↑↑ ILIL--4, IL4, IL--10. It 10. It downregulatedownregulate the stimulatory the stimulatory effect of HCV on effect of HCV on Th1 cytokinesTh1 cytokines and and this may lead to this may lead to chronicitychronicity of HCV of HCV infection in infection in coinfectedcoinfected patients (Elpatients (El--KadyKady et al., 2004& 2005).et al., 2004& 2005).

Prof. Gamal Esmat

EpidemiologyEpidemiology

Effect of Combined infection Effect of Combined infection

–– ImmunopathogenesisImmunopathogenesis

–– SeveritySeverity

–– SVRSVR

Prof. Gamal Esmat

Pathologically Pathologically schistoschisto--HCV coHCV co--infection has infection has possibly a synergistic effect especially on possibly a synergistic effect especially on hepatic fibrosis.hepatic fibrosis.

By serial liver biopsies ,progression of By serial liver biopsies ,progression of hepatic fibrosis was shown to be faster in hepatic fibrosis was shown to be faster in patients with copatients with co--infection than in those infection than in those with HCV (0.6 point/year with HCV (0.6 point/year vsvs 0.2point/year)0.2point/year)

This may refer to altered immune response This may refer to altered immune response or or fibrogenesisfibrogenesis signals.signals.

Prof. Gamal Esmat

Influence Of Combined Influence Of Combined Infection On Infection On The Clinical The Clinical Course Of Liver DiseaseCourse Of Liver Disease

HCV infection causes a HCV infection causes a more severemore severe and and irreversibleirreversible form of liver disease than infection form of liver disease than infection with with S. mansoni. S. mansoni. AngelicoAngelico et al., (1997) et al., (1997)

ComplicationsComplications of cirrhosis were of cirrhosis were more commonmore common in in patients with both diseases than in those with patients with both diseases than in those with either disease alone (either disease alone (KoshyKoshy et al., 1993 and et al., 1993 and Kamal et al., 2000 and Gad et al., 2001).Kamal et al., 2000 and Gad et al., 2001).

Prof. Gamal Esmat

CLDCLDDecompensated

CLD–– ↑↑ grade C Childgrade C Child--Pugh score, Pugh score, –– ↑↑ episodes of upper GI bleeding, episodes of upper GI bleeding, –– ↑↑ renal impairment renal impairment –– ↑↑ mortality rate mortality rate

(Kamal et al., 2000 and Gad et al., 2001). (Kamal et al., 2000 and Gad et al., 2001).

Prof. Gamal Esmat

What about the relation of What about the relation of

combined infection on combined infection on HCC HCC

prevalence ?prevalence ?

HCC is present only in coinfection or HBV HCC is present only in coinfection or HBV

& HCV infection and never observed in & HCV infection and never observed in S. S.

mansonimansoni infection alone (Ahmed et al., infection alone (Ahmed et al.,

(1998) and Kamal et al., 2000).(1998) and Kamal et al., 2000).

Prof. Gamal Esmat

EpidemiologyEpidemiology

Effect of Combined infection Effect of Combined infection

–– ImmunopathogenesisImmunopathogenesis

–– SeveritySeverity

–– Sustained Sustained VirologicalVirological Response (SVR)Response (SVR)

Prof. Gamal Esmat

Is schistosomal infection has Is schistosomal infection has an influence on an influence on

antianti--viral therapy?viral therapy?ELEL--ShazlyShazly et al., (1994); reported et al., (1994); reported low rate of low rate of responseresponse in combined infection than in HCV in combined infection than in HCV alone. alone.

The presence of associated schistosomiasis has The presence of associated schistosomiasis has determined the response of Egyptians with determined the response of Egyptians with chronic hepatitis C to therapy with interferon chronic hepatitis C to therapy with interferon ((AbdelAbdel Basset et al., 1994).Basset et al., 1994).

Prof. Gamal Esmat

Response to INF in subjects Response to INF in subjects with dead and living ova at 24 with dead and living ova at 24

weeks treatmentweeks treatment

5060

10

20

30

40

50

60

70

80

90

100

Living ova Dead ova

Living ova

Dead ova

%

Dead Ova, 22

Living Ova, 14

Living Ova

Dead Ova

Prof. Gamal Esmat

57 64

102030405060708090

100

Had SchistoTTT

Did not haveSchisto TTT

Had Schisto TTTDid not have Schisto TTT

Had Schisto TTT, 86

Did not have Schisto

TTT, 114

%

Response to INF according to Response to INF according to anti anti schistosomalschistosomal treatmnettreatmnet

at 24 weeks treatmentat 24 weeks treatment

Prof. Gamal Esmat

Those who did not receive Those who did not receive parentralparentralantischistosomalantischistosomal therapy( PAT )in the past therapy( PAT )in the past responded to treatment better than those responded to treatment better than those who did. who did. The SVR being 44% in those not The SVR being 44% in those not previously receiving (PAT) and only 30% previously receiving (PAT) and only 30% in those who had been given PAT (p=.07).in those who had been given PAT (p=.07).

EsmatEsmat et al 2003et al 2003

Prof. Gamal Esmat

ConclusionConclusion

Patients coinfected with HCV and schistosomiasis exhibit a unique clinical, virological and histological pattern

Virologially: by viral persistence with high HCV-RNA titres.

Pathologically: higher necroinflammatory and fibrosis scores in their liver biopsy samples.

Prof. Gamal Esmat

ConclusionConclusion

Dual infections of schistosomiasis and viral infections display significant influences on host immune reactions

cytotoxic T-lymphocyte response,Upregulation of Th2 response → Granulomaformation → fibrosisDownregulation of Th1 response→ chronicity of HCV infection

Prof. Gamal Esmat

ConclusionConclusion

The presence of associated The presence of associated schistosomiasis has determined the schistosomiasis has determined the response of Egyptians with chronic response of Egyptians with chronic hepatitis C to therapy with interferonhepatitis C to therapy with interferon

Prof. Gamal Esmat

Thank youThank you

Prof. Gamal Esmat