Chronic hepatitis E after kidneytransplantation with an antibody responsesuggestive of reinfection: a case report
BackgroundHepatitis E virus (HEV) infection is increasingly recognizedas a major cause of acute hepatitis worldwide.
To date, five human pathogenic HEV genotypes are known. The dominant one in Europe is genotype 3 (gt3) which is transmitted zoonotically to humans
HEV infection remains asymptomatic or presents as mild and self-limiting disease.
The humoral immune response begins with the rise of anti-HEV IgMantibodies followed by the development of a robust antiHEV IgG response.
The anti-HEV IgG antibody concentration then slowly declines over time but may remain detectable for years.
In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates. In these patients the HEV specific antibody response is variable or lacking at large.
In the following case report:
The authors reported a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG pre- and post-transplantation and they described and characterized the HEV-specific antibody response over time.
Case presentation:
The authors report an immunocompromised patient who developed chronic HEV infection despite the presence of high level antibodies. HEV infection was detected using RT-PCR upon diagnostic evaluation due toincreased liver enzymes. Upon retrospective analysis of stored serum samples we found that the patient was HEVRNA positive since 7 months. Chronic HEV infection was successfully treated with ribavirin.
For clinical practice the following points remain important:I. The presence of anti-HEV IgG may not beprotective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressiveregimens.II. Clinical work-up upon increased liver enzymesshould include testing for HEV infectionirrespective of the anti-HEV IgG status beforeimmunosuppression.III. In immunosuppressed patients HEV infectionshould be diagnosed using nucleic acid testing.IV. Counseling patients at risk for chronic HEVinfection regarding the consumption of raw/undercooked pig products seems advisable.V. In conclusion, we were able to identify a patientwith HEV reinfection who developed a chroniccourse which was successfully treated withribavirin. The role of the humoral and T-cellmediated immune response in cases of HEVreinfection deserves further study.
Conclusions: In conclusion, the patient suffered from a chronic course of HEV infection, which was successfullytreated with ribavirin. Our case underlines the importance of RT-PCR for HEV diagnostics in immunosuppressedpatients and supports the notion that HEV antibodies do not confer universal protection. Counseling patients at riskfor chronic HEV infection seems advisable. The role of the humoral and T-cell mediated immune response in casesof HEV reinfection deserves further
Chronic hepatitis E after kidneytransplantation with an antibody responsesuggestive of reinfection: a case report
BackgroundHepatitis E virus (HEV) infection is increasingly recognizedas a major cause of acute hepatitis worldwide.
To date, five human pathogenic HEV genotypes are known. The dominant one in Europe is genotype 3 (gt3) which is transmitted zoonotically to humans
HEV infection remains asymptomatic or presents as mild and self-limiting disease.
The humoral immune response begins with the rise of anti-HEV IgMantibodies followed by the development of a robust antiHEV IgG response.
The anti-HEV IgG antibody concentration then slowly declines over time but may remain detectable for years.
In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates. In these patients the HEV specific antibody response is variable or lacking at large.
In the following case report:
The authors reported a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG pre- and post-transplantation and they described and characterized the HEV-specific antibody response over time.
Case presentation:
The authors report an immunocompromised patient who developed chronic HEV infection despite the presence of high level antibodies. HEV infection was detected using RT-PCR upon diagnostic evaluation due toincreased liver enzymes. Upon retrospective analysis of stored serum samples we found that the patient was HEVRNA positive since 7 months. Chronic HEV infection was successfully treated with ribavirin.
For clinical practice the following points remain important:I. The presence of anti-HEV IgG may not beprotective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressiveregimens.II. Clinical work-up upon increased liver enzymesshould include testing for HEV infectionirrespective of the anti-HEV IgG status beforeimmunosuppression.III. In immunosuppressed patients HEV infectionshould be diagnosed using nucleic acid testing.IV. Counseling patients at risk for chronic HEVinfection regarding the consumption of raw/undercooked pig products seems advisable.V. In conclusion, we were able to identify a patientwith HEV reinfection who developed a chroniccourse which was successfully treated withribavirin. The role of the humoral and T-cellmediated immune response in cases of HEVreinfection deserves further study.
Conclusions: In conclusion, the patient suffered from a chronic course of HEV infection, which was successfullytreated with ribavirin. Our case underlines the importance of RT-PCR for HEV diagnostics in immunosuppressedpatients and supports the notion that HEV antibodies do not confer universal protection. Counseling patients at riskfor chronic HEV infection seems advisable. The role of the humoral and T-cell mediated immune response in casesof HEV reinfection deserves further study.
A 64-year-old man who has kidney transplantation in April 2016 who had elevated AST (62 U/L, normal range < 50 U/L), ALT (81 U/L, normal range < 50 U/L), and γ-GT (276 U/ L, normal range < 60 U/L) on routine testing on nov 2016. In March 2017, he had γ-GT with 215 IU/ L, but AST (44 U/L) and ALT (45 U/L) returned back to normal range. HEV RNA was detected using RT-PCR . Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection. Interestingly, stored plasma samples taken before kidney transplantation were positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before transplantation. In September 2017, treatment with ribavirin (200 mg, 5 doses daily) was initiated. His liver values were AST (77 U/ L), ALT (78 U/L), and γ-GT (226 U/L). He received an 11- week course of ribavirin (off-label use) and therapy was stopped due to anemia.
This case illustrates that the work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
HEV infection –one of the causes of acute hepatitis globally but it can progress to chronic hepatitis in some cases with high morbidity and mortality. To date, five genotypes have been known. Less than 1-52% patients have been found positive for HEV in Europe. Anti-HEV antibody persists throughout life but had controversial opinion about conferring protection against re-infection. Aim of the study:
A case report of renal transplant patient who developed chronic HEV infection shortly after transplant despite the presence of high level antibodies. Case presentation
A 64 year female was started on triple immunosuppression including tacrolimus, mycophenolate, and prednisolone after renal transplant. Primary cause of ESRD was FSGS.FSGS recurred after transplant and treated with therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as replacement fluid. Later also given rituximab 750 mg twice to achieve remission which was achieved in in June 2016.Three months later developed BK viremia for which immunosuppression(MMF) was reduced and IVIG administered ,copies of BK virus becomes undetectable. In November 2016, patient had elevation of liver function ALT ,AST and gamma GT .HEV RNA was being advised and comes out to be positive along with anti-HEV IgM and IgG using ELISA indicating active HEV infection. Patient was being treated with Ribavirin for 11 months after which it was stopped due to anemia. Liver function tests and PCR for HEV RNA becomes negative after treatment. CONCLUSION:
No long lasting protection due to anti-HEV antibodies.
Counseling to avoid raw or under cooked animal products.
HEV RNA PCR is essential and should be done in cases of liver dysfunction.
Ribavirin is the only treatment option available.
Summarise this article:
Patient had an ESRD due to FSGS, had an acute rejection due to recurrence of FSGS, for which he received PF and rituximab, He also had BKV infection which respond to IS reduction.
Patient developed an elevation of liver enzyme he found to have HEV infection by HED RNA.
Stored plasma shows HEV IgG, but no evidence of IGM, which imply previous infection.
Patient received Ribavirin to treat HEV infection, though he developed anemia, which necessities scission of medication, he respond to treatment. Conclusion:
IgG against HEV not confer protection against HEV reinfection.
HEV RNA and/or antigen detection must be used to diagnose HEV.
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation, treatment available is Ribavirin, which should be follow for anemia complication.
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report.
Background
Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide. There is a five human pathogenic HEV genotypes are known, of which HEV genotype 3 (gt3) is the dominant HEV genotype in Europe.
HEVgt3 is transmitted zoonotically to humans and infections are linked to the consumption of HEV contaminated meat products. In general, HEV infection remains asymptomatic or presents as mild and self-limiting disease.
In immunosuppressed patients, , acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates. in these patients the HEV specific anti body response is variable or lacking at large.
Case presentation
A 64-year-old man with a history of focal segmental glomerulosclerosis underwent kidney transplantation in April 2016. Immunosuppressive medication after trans plantation
included tacrolimus, mycophenolate mofetil and prednisone. In addition, he received rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as replacement fluid due to recurrence of focal segmental glomerulosclerosis, which subsequently resolved until October 2016. His post-transplantation course showed BKV viremia three months after transplantation. Which is controlled with reduction of immunosuppression. Intravenous immune globulins (10 g) were given once at the end of June 2016 due to hypogammaglobulinemia.
in November 2016, routine laboratory testing revealed elevated AST, ALT, and gamma –GT. HEV RNA was detected using RT-PCR. Concomitantly anti-HEV IgM and IgG were positive.
Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection.
stored plasma samples taken before kidney transplantation were positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before trans plantation.
In September 2017, treatment with ribavirin (200 mg, 5doses daily) was initiated.
discussion and conclusions:
this article show a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation. This suggests HEV re-infection and indicates that HEV antibodies did not confer protection in this patient.
HEV antibodies have been standardized and a minimum protective antibody concentration of 2.5 (WHO)
units/mL has been proposed. However, a definitive protective titer has not been firmly assessed yet.
Beyond the humoral response and the immunosuppressive therapy chronic HEV infection has been associated with an impaired HEV-specific T-cell response in transplant patients.
Cases of reactivation of HEV have been rarely described to date . We did not detect HEV RNA before and shortly after transplantation arguing against reactivation in this patient.
This patient developed chronic HEV infection which can lead to rapidly developing cirrhosis and liver failure.
Treatment with ribavirin was successful in this patient but anemia as well-known side effect of ribavirin led to the discontinuation of antiviral therapy. Currently, ribavirin is the only drug available for treatment of HEV infection.
Important clinical practice point:
I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti- HEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
V. In conclusion, this article identify a patient with HEV reinfection who developed a chronic course which was successfully treated with ribavirin.
Summarise this article; This article discus the chronic HEV infection of a case with post-transplantation, this is a case of a 64-years –old man with history of FSGS was transplanted and received immunosuppression. Now recurrence of disease started treated as rejection, then BK viremia, improved. Now presented with elevated transaminases with clinical symptoms, Further workup done showed HEV RNA PCR positive. In September 2017, the recipient was given ribavirin for 11 weeks, although treatment was stopped to Anemia. However, in October the enzymes become normal and HEV PCR become negative. Discussion, conclusion; According to WHO the minimal protective threshold for anti-HEV titers should be >6 units/ml to give protection. Only treatment is ribavirin, However, the case report demonstrate that anti-HEV IgG may not be protective in immunosuppressed patient. It’s crucial to advice the recipient about diet.
A 64-year-old man with a history of focal segmental glomerulosclerosis underwent kidney transplantation and received immunosuppressive medication. After transplantation, he had BKV viremia which was managed by adjusting the dosage of the immunosuppressive medication. In November 2016, routine laboratory testing revealed elevated liver enzymes and HEV RNA was detected using RT-PCR indicating active HEV infection. Concomitantly, anti-HEV IgM and IgG were positive. Retrospective analysis showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection. Treatment with ribavirin was initiated, and therapy was stopped due to anemia. HEV RNA in plasma was first negative in October 2017 and remained negative indicating successful therapy. The mode of acquisition of HEV infection in this patient remains unclear but could be related to HEV-contaminated blood products, an HEV-contaminated transplant organ, or food uptake after transplantation.
This article reports a case of chronic HEV infection that occurred shortly after KTX despite the presence of high titer of anti-HEV IgG pre- & post transplantation.
HEV-infection is considered as a major cause of acute hepatitis worldwide. It has 5 genotypes gt 3 is the dominant in Europe and cause mild and self-limiting symptoms. Mode of transmission through orofecal route and row meat. IgM and IgG antibodies against HEV develops because of humoral immune response, and these antibodies stays for years. Acute HEV gt3 infection can proceed to a chronic course in immunosuppressed patients, which can result in substantial morbidity and mortality. Even with high levels of anti-HEV IgG antibodies, this case study reveals the development of chronic HEV infection in immunosuppressed patient. Case presentation: A 64-year-old man with focal segmental glomerulosclerosis (FSGS) on tacrolimus-based triple drug immunosuppression having history of FSGS recurrence post-transplant treated with plasmapheresis and rituximab, subsequently developed BK viremia then improved now experienced elevated liver enzymes (AST, ALT, and GGT) in November 2016 without clinical symptoms. Despite AST and ALT returning to normal in March 2017, GGT remained high. On further work up HEV RNA PCR, anti-HEV IgM, and anti-HEV IgG were positive with HEV genotype 3c type. Retrospective blood sample analysis found positive HEV RNA in a sample taken in September 2016 and positive anti-HEV IgG with negative anti-HEV IgM and HEV RNA in a sample taken before the transplant. Anti-HEV IgM levels increased concurrently with a sharp rise in anti-HEV IgG up until February 2017. In September 2017, the patient underwent an 11-week course of ribavirin treatment before the treatment was stopped due to anemia. In October 2017, liver enzymes returned to normal and plasma HEV RNA became negative. Discussion: HEV antibodies are considered to be pivotal to control the infection. A minimal protective threshold of 2.5 WHO units/mL for anti-HIV antibodies has been proposed. Anti-HEV IgG titers below 6 IU/mL (or 7 WHO units/mL) have been proven to not protect against HEV reinfection. Anti-HEV antibodies in the index patient were 7 IU/ml and were therefore not protective Ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently need. In conclusion, this report illustrates that anti-HEV IgG may not be protective in immunosuppressed patients. Suspected cases should undergo HEV NAT testing, Dietary counseling regarding consumption of raw or undercooked meat (pig) is crucial, and HEV reinfection can be successfully treated with ribavirin.
HEV specific antibodies develop shortly after infection and are thought to confer protection.Authors reported a case of kidney transplant recipient chronic HEV infection despite the presence of high level antibodies. . Upon retrospective analysis of stored serum samples they found that the patient was HEV RNA positive since 7 months but have high level IgG antibody. HEV infection was detected using RT-PCR upon diagnostic evaluation due to increased liver enzymes..Chronic HEV infection was successfully treated with ribavirin.
For clinical practice the following points remain important:
I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide. To date, five humans pathogenic HEV genotypes are known, of which HEVgenotype3(gt3)isthedominantHEVgenotypein Europe.
Recent data demonstrated HEV seroprevalence rates ranging from < 1% up to 52% across Europe.
HEV gt3 is transmitted zoonotically to humans and infections are linked to the consumption of HEV contaminated meat products. In general, HEV infection remains asymptomatic or presents as mild and self-limiting disease. The humoral immune response begins with the rise of anti-HEV IgM antibodies followed by the development of a robust antiHEV IgG response.
Discussion and conclusions
Here, we were able to show a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation. This suggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient. Cases of HEV reinfection leading to chronic courses have been described anecdotally but comprehensive data is lacking at large.
HEV antibodies are considered to be pivotal to control the infection.
Recently, HEV antibodies have been standardized and a minimum protective antibody concentration of 2.5 World Health Organization (WHO) units/mL has been proposed.
However, a definitive protective titer has not been firmly assessed yet. Choi and coworkers recently demonstrated that rhesus macaques with low HEV-IgG titers (< 6 IU/ml) were not protected against HEV reinfection.
As a caveat, HEV serological assays differ in their performance and standardization of antibody assays is under debate, e. g. for rubella.
Interestingly, our patient showed a rapid rise in anti-HEV IgG which was followed by an anti-HEV IgM response shortly after. This pattern is typical for a booster immune response and has been demonstrated for HEV in vivo.
However, despite the rapid anti-HEV IgG response this did not lead to clearance of HEV RNA from the blood in our patient. This further supports the notion of a limited protective humoral immune response.
Interestingly, the rituximab induced B cell depletion might have influenced the development of HEV antibodies in our patient, but anti-HEV IgG levels did never fall below the cut-off of the assay.
Beyond the humoral response and the immunosuppressive therapy chronic HEV infection has been associated with an impaired HEV-specific T-cell response in transplant patients
However, the T-cell mediated immune response remains largely unclear in HEV infection and deserves further study. We were able to show that the HEV-specific CD8+ Tcell response in chronic HEV patients was diminished in comparison to the acute disease course but was partially restored after ribavirin therapy (own unpublished data). For clinical practice the following points remain important:
I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
V. In conclusion, we were able to identify a patient with HEV reinfection who developed a chronic course which was successfully treated with ribavirin. The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
Summarize this article
Background – HEV is a major cause of hepatitis worldwide, transmitted through feco-oral route and consumption of contaminated meat products – Of the 5 genotypes, Genotype-3 is commonest in Europe – HEV infection remains asymptomatic or presents as mild and self-limiting disease. – In immunocompromised patients, acute infection by HEV genotype 3 can progress to chronicity (anti-HEV Abs detectable >6months), associated with high morbidity and mortality. – Immune response starts with anti-HEV IgM antibodies followed by anti-HEV IgG, which declines over time but may remain detectable for years, and whether HEV specific antibodies confer any protection is controversial. Case presentation – 64years male FSGS – ESRD patient, underwent kidney transplant in April 2016, on triple drug regimen – June 2016: recurrent FSGS treated with rituximab (750mgx2), 26 plasma exchange and 10gm IVIg (for hypogammaglobulinemia).
– July 2016: due to intense IS, he developed BKV viremia (383,500 copies/mL) à responded to reduced IS (prednisone tapered to 10mg/d, MMF reduced to 250mg BD) à BKV resolved (<1000 copies/mL) from Oct 2016 onwards; then MMF was increased to 500mg BD; also, FSGS resolved until Oct 2016.
– November 2016: elevated liver enzymes: AST 62, ALT 81, GGT 276, with a normal liver ultrasound – March 2017: he was doing well, on tacrolimus 1mg BD, trough level 5-8ng/mL, MMF 500mg BD, prednisone 7.5mg/d; normal AST (44) & ALT (45), but elevated GGT (215) and liver ultrasound. HCV RNA was negative, HEV RNA,anti-HEV IgM and IgG positive – indicating an active HEV infection. – retrospective analysis of stored plasma samples revealed positive HEV RNA since September 2016 indicating chronic HEV infection – stored pre-transplant plasma samples were positive for anti-HEV IgG but negative for anti-HEV IgM and HEV RNA indicating resolved HEV infection before transplantation – there was a rapid rise in anti-HEV IgG after HEV RNA was first detected in September 2016 but anti-HEV IgM remained negative
– February 2017: positive anti-HEV IgM and IgG à indicated reactivation of active HEV infection – September 2017: Ribavirin therapy (200mg 5 doses daily) initiated; liver enzymes partially elevated (AST 77, ALT 78, GGT 226); but therapy was stopped at 11 weeks due to severe anaemia. – October 2017: plasma HEV RNA became negative and remained negative throughout with normal liver enzymes, indicating successful response to therapy (SVR).
Discussion – mode of HEV infection acquisition in this patient remains unknown – could be due to an HEV-contaminated transplant organ, contaminated blood products, consumption of contaminated food post-transplant
– The patient had chronic HEV infection in spite of detectable anti-HEV IgG before and after kidney transplantation – Anti-HEV-IgG Abs might control HEV infection, and a minimum protective concentration of 2.5units/mL has been proposed. – Anti-HEV Abs did not confer protection in this patient, resulting in a chronic HEV infection – Rituximab induced B cell depletion might have contributed to the reinfection in spite of the presence of Anti-HEV Abs. – Immunosuppressive therapy affecting humoral response can result in a decrease in the anti-HEV IgG titres after transplantation – Immunosuppressive therapy impairs HEV-specific T-cell response in transplant recipients. Tacrolimus is thought to promote infection of hepatocytes with HEV, MMF inhibits HEV replication, while steroids showed no effect at all – this index patient most likely had HEV reactivation, since HEV RNA remained undetectable before and shortly after transplantation – few cases of HEV reactivation have been described in literature – chronic HEV infection can result in liver cirrhosis and liver failure – this patient responded well to ribavirin, although the therapy discontinued due to anaemia – Ribavirin is currently the only drug available for treatment of HEV infection in transplant recipients – Peg-interferon has antiviral activity against HEV but can’t be used due to high risk of rejection – Sofosbuvir, a proteosome inhibitor of HCV, may be effective but more studies are needed on its use in HEV Conclusion – presence of anti-HEV IgG may not confer protection this therefore limits the significance of testing anti-HEV IgG pre-transplant/ before initiating immunosuppressive therapy – in patients with elevated liver enzymes, screen for HEV infection regardless of the anti-HEV IgG status before immunosuppression – NAT (nucleic acid testing) is useful to diagnose HEV infection in immunocompromised patients – counsel/ educate patients at risk for chronic HEV infection about consumption of raw/ undercooked pork products – role of T-cell mediated and humoral immune response in HEV reinfection requires further research
Background:
HEV-infection is considered as a major cause of acute hepatitis worldwide.
It has 5 genotypes gt 3 is the dominant in Europe and cause mild and self-limiting symptoms.
Mode of transmission through orofecal route and row meat.
IgM and IgG antibodies against HEV develops because of humoral immune response, and these antibodies stays for years.
Acute HEV gt3 infection can proceed to a chronic course in immunosuppressed patients, which can result in substantial morbidity and mortality.
Even with high levels of anti-HEV IgG antibodies, this case study reveals the development of chronic HEV infection in immunosuppressed patient. Case presentation:
A 64-year-old man with focal segmental glomerulosclerosis (FSGS) on tacrolimus-based triple drug immunosuppression having history of FSGS recurrence post-transplant treated with plasmapheresis and rituximab, subsequently developed BK viremia then improved now experienced elevated liver enzymes (AST, ALT, and GGT) in November 2016 without clinical symptoms. Despite AST and ALT returning to normal in March 2017, GGT remained high.
On further work up HEV RNA PCR, anti-HEV IgM, and anti-HEV IgG were positive with HEV genotype 3c type. Retrospective blood sample analysis found positive HEV RNA in a sample taken in September 2016 and positive anti-HEV IgG with negative anti-HEV IgM and HEV RNA in a sample taken before the transplant.
Anti-HEV IgM levels increased concurrently with a sharp rise in anti-HEV IgG up until February 2017. In September 2017, the patient underwent an 11-week course of ribavirin treatment before the treatment was stopped due to anemia. In October 2017, liver enzymes returned to normal and plasma HEV RNA became negative. Discussion:
HEV antibodies are considered to be pivotal to control the infection.
A minimal protective threshold of 2.5 WHO units/mL for anti-HIV antibodies has been proposed. Anti-HEV IgG titers below 6 IU/mL (or 7 WHO units/mL) have been proven to not protect against HEV reinfection. Anti-HEV antibodies in the index patient were 7 IU/ml and were therefore not protective
Ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently need.
In conclusion, this report illustrates that anti-HEV IgG may not be protective in immunosuppressed patients. Suspected cases should undergo HEV NAT testing,
Dietary counseling regarding consumption of raw or undercooked meat (pig) is crucial, and HEV reinfection can be successfully treated with ribavirin.
The zoonotic transmission of acute hepatitis caused by the hepatitis E virus (HEV)
five genotypes transmission mode is infected meat products and orofecal roots.
genotype 3 is more common in Europe, typically results in a mild, self-limiting sickness.
IgM and IgG antibodies against HEV develops because of humoral immune response, and these antibodies stays for years.
Acute HEV gt3 infection can proceed to a chronic course in immunosuppressed patients, which can result in substantial morbidity and mortality.
Even with high levels of anti-HEV IgG antibodies, this case study reveals the development of chronic HEV infection in immunosuppressed patient.
Case presentation
A 64-year-old man with focal segmental glomerulosclerosis (FSGS) on tacrolimus-based triple drug immunosuppression having past history of FSGS recurrence post-transplant treated with plasmapheresis and rituximab, subsequently developed BK viremia then improved now experienced elevated liver enzymes (AST, ALT, and GGT) in November 2016 without clinical symptoms. Despite AST and ALT returning to normal in March 2017, GGT remained high.
On further work up HEV RNA PCR, anti-HEV IgM, and anti-HEV IgG were positive with HEV genotype 3c type. Retrospective blood sample analysis found positive HEV RNA in a sample taken in September 2016 and positive anti-HEV IgG with negative anti-HEV IgM and HEV RNA in a sample taken before the transplant.
Anti-HEV IgM levels increased concurrently with a sharp rise in anti-HEV IgG up until February 2017. In September 2017, the patient underwent an 11-week course of ribavirin treatment before the treatment was stopped due to anemia. In October 2017, liver enzymes returned to normal and plasma HEV RNA became negative. Discussion
The anti-HEV antibodies do not provide protection against HEV reinfection in most cases.
A minimal protective threshold of 2.5 WHO units/mL for anti-HIV antibodies has been proposed. Anti-HEV IgG titres below 6 IU/mL (or 7 WHO units/mL) have been proven to not protect against HEV reinfection. Anti-HEV antibodies in the index patient were 7 IU/ml and were therefore not protective.
The use of rituximab due to multiple indications resulted in B cell reduction and ultimately can led to reinfection even in the presence of anti-HEV antibodies.
Anti-HEV antibodies gets decreased post-transplant due to immunosuppressive drugs, this compromises the ability to prevent HEV reinfection. beside that it has been demonstrated that tacrolimus increases HEV infection in hepatic cells, whereas MMF suppresses HEV proliferation.
Poor T cell response to HEV also plays a role in HEV reinfection.
In conclusion, this report illustrates that anti-HEV IgG may not be protective in immunosuppressed patients. Suspected cases should undergo HEV NAT testing,
dietary counseling regarding consumption of raw or undercooked meat (pig) is crucial, and HEV reinfection can be successfully treated with ribavirin.
IV. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
Summarise this article
Background
– HEV is a major cause of hepatitis worldwide
– 5 genotypes have been described
– transmission is through consumption of contaminated meat products
– HEV specific antibodies develop after HEV infection and are thought to confer protection, although this remains controversial
– the minimum protective HEV Ab concentration is yet to be established
– HEV infection presents as a mild self-limiting disease or remains asymptomatic
– anti-HEV IgM Abs are usually the first to rise followed by anti-HEV IgG Abs
– anti-HEV IgG Ab levels decline over time but may remain detectable for years
– among immunocompromised patients, active HEV genotype 3 infection can progress to a chronic infection with HEV Abs remaining detectable for >6months
– it is associated with high morbidity and mortality
Case presentation
– 64yo man, FSGS, kidney transplantation in April 2016
– immunosuppressive regimen: tacrolimus, mycophenolate mofetil, prednisone
– June 2016 had FSGS recurrence: received rituximab 750mg twice, therapeutic plasma exchange (TPE) 26 times with albumin and FFPs as replacement fluid
– June 2016 had hypogammaglobulinemia: given IVIG 10g
– July 2016 had BKV viremia (383,500 copies/mL): prednisone was tapered to 10mg/d, MMF reduced to 250mg BD
– from October 2016 onwards, plasma BKV viremia remained <1000 copies/mL and MMF was increased to 500mg BD
– the recurrent FSGS resolved until October 2016
– November 2016 had elevated liver enzymes: AST 62, ALT 81, GGT 276, with a normal liver ultrasound
– March 2017, doing well on tacrolimus 1mg BD, trough level 5-8ng/mL, MMF 500mg BD, prednisone 7.5mg/d, normal AST 44, normal ALT 45, elevated GGT 215, with a normal abdominal ultrasound, HCV RNA negative, HEV RNA positive indicating an active HEV infection, anti-HEV IgM and IgG were also positive
– retrospective analysis of stored plasma samples revealed positive HEV RNA since September 2016 indicating chronic HEV infection
– stored pre-transplant plasma samples were positive for anti-HEV IgG but negative for anti-HEV IgM and HEV RNA indicating resolved HEV infection before transplantation
– there was a rapid rise in anti-HEV IgG after HEV RNA was first detected in September 2016 but anti-HEV IgM remained negative
– February 2017: positive anti-HEV IgM, positive anti-HEV IgG
– September 2017: initiated on ribavirin 200mg 5 doses daily; AST 77, ALT 78, GGT 226, was on ribavirin for 11 weeks, therapy was stopped due to anaemia
– October 2017: negative plasma HEV RNA (for the first time), it remained negative indicating successful response to therapy, liver enzymes normalized
– mode of HEV infection acquisition in this patient remains unknown but could be due to an HEV-contaminated transplant organ, contaminated blood products, consumption of contaminated food post-transplant
Discussion
– this patient had chronic HEV infection in spite of detectable anti-HEV IgG before and after kidney transplantation suggesting HEV reinfection
– this indicates that the HEV Abs did not confer protection in this particular patient resulting in a chronic HEV infection
– HEV Abs are key in controlling the infection
– a minimum protective antibody concentration of 2.5units/mL has been proposed
– the rituximab induced B cell depletion might have contributed to the reinfection in spite of the presence of HEV Abs
– immunosuppressive therapy affects the humoral response and this can result in a decrease in the anti-HEV IgG titers shortly after transplantation
– tacrolimus is thought to promote infection of hepatocytes with HEV, MMF inhibits HEV replication, while steroids showed no effect at all
– immunosuppressive therapy impairs HEV-specific T-cell response in transplant recipients
– few cases of HEV reactivation have described in literature
– most likely this patient had HEV reactivation since HEV RNA remained undetectable before and shortly after transplantation
– chronic HEV infection can result in liver cirrhosis and liver failure
– this patient responded well to ribavirin unfortunately he developed anaemia warranting discontinuation of the antiviral therapy
– ribavirin is currently the only drug that is available for treatment of HEV infection
– pegylated interferon has antiviral activity against HEV but it cannot be used in HSCT or SOT recipients due to a high risk of rejection
– sofosbuvir, a proteosome inhibitor of HCV, may be effective but more studies are needed to support its use
Conclusion
– presence of anti-HEV IgG may not confer protection this therefore limits the significance of testing anti-HEV IgG pre-transplant/ before initiating immunosuppressive therapy
– in patients with elevated liver enzymes screen for HEV infection regardless of the anti-HEV IgG status before immunosuppression
– use NAT (nucleic acid testing) to diagnose HEV infection in immunocompromised patients
– counsel/ educate patients at risk for chronic HEV infection about consumption of raw/ undercooked pork products
– role of T-cell mediated and humoral immune response in HEV reinfection requires further research
Background
· Five human pathogenic HEV genotypes are known, of which HEV genotype 3 is the commonest in Europe.
· HEV infection remains asymptomatic or presents as mild and self-limiting disease.
· Response started with anti-HEV IgM antibodies followed by antiHEV IgG, which declines over time but may remain detectable for years.
· In immunosuppressed patients, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates.
Case presentation
· A 64-year-old man with a history of FSGS, recurrence of FSGS post transplant, given rituximab 750 mg twice and therapeutic plasma exchange, and maintained on Tacrolimus, MMF, and prednisone.
· post-transplantation course showed BKV viremia three months after transplantation, so MMF was reduced to a dose of 250 mg twice daily.
· BKV viremia remained below 1000 copies/mL, so MMF was increased to 500 mg twice daily.
· After that routine lab found: AST 62 U/L, ALT 81 U/L, and γ-GT 276 U/ L.
· Ultrasound of the liver showed no pathological findings.
· Testing for hepatitis C virus RNA was negative, however, HEV RNA was detected using RT-PCR.
· Concomitantly anti-HEV IgM and IgG using ELISA were positive.
· Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months indicating chronic HEV infection
· Anti-HEV IgG showed a rapid rise after HEV RNA was first detectable, while anti-HEV IgM remained negative.
· Ribavirin (200 mg, 5 doses daily) was given for 11- weeks and was stopped due to anemia.
· HEV RNA in plasma became negative, and Liver enzymes normalized.
Discussion and conclusions
· This is a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation.
· Testing for anti-HEV IgG before the start of immunosuppressive regimens has no value.
· Testing for HEV infection indicated for recipients with elevated liver enzymes.
· In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
· Counseling patients at risk for chronic HEV infection to stop eating raw pig products seems.
● Hepatitis E virus (HEV) infection is a major cause of acute hepatitis worldwide.
● Five HEV genotypes are known
● prevalence ranging from < 1% up to 52%
● Transmitted to humans by HEV contaminated meat products.
● HEV infection is asymptomatic or mild and self-limiting disease.
● In immunosuppressed patients acute HEV gt3 infection can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality
● Here a case of a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG pre- and posttransplant
Case presentation
☆ A 64-year-old man with FSGS
☆ kidney transplantation
☆ IS medication ( tac, MMF, pred )
☆ He received RTX 750 mg 2 doses besides PE for treatment recurrence FSGS
☆ He had BKV viremia three months after transplantation (DNA concentration 383,500 copies/mL).
☆ IS ( pred and MMF ) have reduced and viremia remained below 1000 copies/mL plasma then mycophenolate mofetil was
increased to 500 mg twice daily.
☆ Due to hypogammaglobulinemia IVIG (10 g) were given
☆ Routine laboratory testing revealed elevated AST, ALT and γ-GT
☆ Liver Ultrasound is normal
☆ Testing for hepatitis C virus RNA was negative
☆ HEV RNA was detected indicating active HEV infection.
☆ Anti-HEV IgM and IgG were positive.
☆ stored plasma samples taken before kidney transplantation were positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before transplantation
☆ A rise in HEV IgG occurred parallel to the increase seen with the Mikrogen ELISA.
☆ Yreatment of ribavirin (200 mg, 5 doses daily) was initiated for 11-week then stopped due to anemia.
☆ HEV RNA in plasma was negative and remained negative indicating successful therapy.
☆ Liver enzymes returned back to normal
☆ The mode of acquisition of HEV infection in this patient remains unclear but could be related to HEV- contaminated blood products, an HEV-contaminated transplant organ, or food uptake after transplantation.
Discussion and conclusions
● A case of chronic HEV infection despite the presence of anti-HEV IgG before and after kidney transplantation.
● HEV antibodies did not give patient protection
● low HEV-IgG titers (< 7 IU/ml) were not protected against HEV reinfection
● Despite rapid anti-HEV IgG response it did not lead to clearance of HEV RNA from the blood
● Functional B cells are instrumental to control the infection and antibodies might not be the only correlate of protection
● A nti-HEV IgG titers decreased shortly after transplantation suggestion an influence of the immunosuppressive therapy on the humoral immune response.
● Tacr promoted the infection of liver cells with HEV whereas MMF inhibited HEV replication and steroids showed no effect
● Chronic HEV infection impairs HEV-specific T-cell response in transplant patients
● Ribavirin is the only drug available for treatment of HEV infection
● Pegylated interferon-alfa has antiviral activity against HEV but cannot be used in transplants due to a high risk of rejection.
● Important clinical practice points :
I. The presence of anti-HEV IgG may not be
protective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/undercooked pig products seems advisable.
V. In conclusion, we were able to identify a patient with HEV reinfection who developed a chronic course which was successfully treated with ribavirin.
HEV gt3 IS COMMON GENOTYPE
ANTI HEV IM AND then IG antibodies are developed in response to acute HEV infection
HEV transmission is through contaminated meat
Antibodies are thought to protect aging infection but this fact is not proven yet
index case represent acute HEV infection in post transplant scenario inspite of ANTI HEV antibody
so monitoring HEV RNA in serum in indicated cases( symptomatic and raised liver enzymes ) is MUST
index case had HEV RNA before the transplant indicating chronic HEV infection and antibodies were not neutralizing and were not effective.
Treatment of index case
ribavarin 200 mg 5 times a day , 11 weeks
stopped due to anaemia , commonest AE
conclusion
case of chronic HEV in spite of anti HEV IG
this suggest REINFECTION with HEV
Protective level of 2.4 WHO units /ml was proposed BUT it is not clear yet
IS drugs reduces the level of antibody post transplant
IS drugs may alter the chances of HEV to enter the liver cells like TACROLIMUS may enhance the entry of virus into the cell
. Clinical work-up upon increased liver enzymes
should include testing for HEV infection
irrespective of the anti-HEV IgG status before
immunosuppression
*This study reported a patient who developed chronic HEV infection shortly PKT despite the presence of high anti-HEV IgG pre- and post-transplantation and described and characterized the HEV-specific antibody response over time.
*Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
*To date, five human pathogenic HEV genotypes are known, of which HEV genotype 3 (gt3) is the dominant HEV genotype in Europe.
* Recent data demonstrated HEV seroprevalence rates ranging from < 1% up to 52% across Europe. *HEV infection remains asymptomatic or presents as mild and self-limiting disease.
*The humoral immune response begins with the rise of anti-HEV IgM antibodies followed by the development of a robust anti- HEV IgG response.
*The anti-HEV IgG antibody concentration then slowly declines over time but may remain detectable for years.
*In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates, and the HEV specific antibody response is variable or lacking at large.
Case presentation:
*The study report an immunocompromised patient who developed chronic HEV infection despite the
presence of high level antibodies.
*The HEV infection was detected using RT-PCR upon diagnostic evaluation due to increased liver enzymes.
*Upon retrospective analysis of stored serum samples they found that the patient was HEV RNA positive since 7 months. Chronic HEV infection was successfully treated with ribavirin.
# Discussion:
*The study showed HEV reinfection and indicates that HEV antibodies did not confer protection in this patient.
*HEV antibodies are considered to be pivotal to control the infection.
*Concentration of 2.5 (WHO) units/mL has been proposed. However, a definitive protective
titer has not been firmly assessed yet
# For clinical practice the following points remain important:
I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti- HEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
V. In conclusion, we were able to identify a patient with HEV reinfection who developed a chronic
course which was successfully treated with ribavirin. The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
# Conclusions:
*The patient suffered from a chronic course of HEV infection, which was successfully treated with ribavirin.
*The study case underlines the importance of RT-PCR for HEV diagnostics in immunosuppressed patients and supports the notion that HEV antibodies do not confer universal protection.
*Counseling patients at risk for chronic HEV infection seems advisable.
*The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide. To date, five human pathogenic HEV genotypes are known, of which HEV genotype 3 (gt3) is the dominant HEV genotype in Europe.
The humoral immune response begins with the rise of anti-HEV IgM antibodies followed by the development of a robust antiHEV IgG response.
The anti-HEV IgG antibody concentration then slowly declines over time but may remain detectable for years.
In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality rates.
For clinical practice the following points remain important:
I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
V. In conclusion, we were able to identify a patient with HEV reinfection who developed a chronic course which was successfully treated with ribavirin. The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
Background
HEV is a zoonotic disease with orofeack rate transmission.
This case study proves that in the case of post-RTX and immunosuppressed individuals, we may have reinfection of HEV despite being immunised, but this patient adding to the IS that he is taking, he did PEX and IV rituximab for his FSGN disease, which will affect his humoral immunity as well. This patient, despite having Anti HEVAb IgG, failed to confer immunity and protect himself and developed high ALLT and GGT with no finding in the US abdomen.
This type of infection has happened as reinfection evidenced by the reappearance of Anti HEVAb IgM level in the serum.
In conclusion, this report illustrates that anti-HEV IgG may not be protective in immunosuppressed patients. Suspected cases should undergo HEV NAT testing,
The zoonotic transmission of acute hepatitis caused by the hepatitis E virus (HEV)
five genotypes transmission mode is infected meat products and orofecal roots.
genotype 3 is more common in Europe, typically results in a mild, self-limiting sickness.
IgM and IgG antibodies against HEV develops because of humoral immune response, and these antibodies stays for years.
Acute HEV gt3 infection can proceed to a chronic course in immunosuppressed patients, which can result in substantial morbidity and mortality.
Even with high levels of anti-HEV IgG antibodies, this case study reveals the development of chronic HEV infection in immunosuppressed patient.
Case presentation
A 64-year-old man with focal segmental glomerulosclerosis (FSGS) on tacrolimus-based triple drug immunosuppression having past history of FSGS recurrence post-transplant treated with plasmapheresis and rituximab, subsequently developed BK viremia then improved now experienced elevated liver enzymes (AST, ALT, and GGT) in November 2016 without clinical symptoms. Despite AST and ALT returning to normal in March 2017, GGT remained high.
On further work up HEV RNA PCR, anti-HEV IgM, and anti-HEV IgG were positive with HEV genotype 3c type. Retrospective blood sample analysis found positive HEV RNA in a sample taken in September 2016 and positive anti-HEV IgG with negative anti-HEV IgM and HEV RNA in a sample taken before the transplant.
Anti-HEV IgM levels increased concurrently with a sharp rise in anti-HEV IgG up until February 2017. In September 2017, the patient underwent an 11-week course of ribavirin treatment before the treatment was stopped due to anemia. In October 2017, liver enzymes returned to normal and plasma HEV RNA became negative.
Discussion
The anti-HEV antibodies do not provide protection against HEV reinfection in most cases.
A minimal protective threshold of 2.5 WHO units/mL for anti-HIV antibodies has been proposed. Anti-HEV IgG titres below 6 IU/mL (or 7 WHO units/mL) have been proven to not protect against HEV reinfection. Anti-HEV antibodies in the index patient were 7 IU/ml and were therefore not protective.
The use of rituximab due to multiple indications resulted in B cell reduction and ultimately can led to reinfection even in the presence of anti-HEV antibodies.
Anti-HEV antibodies gets decreased post-transplant due to immunosuppressive drugs, this compromises the ability to prevent HEV reinfection. beside that it has been demonstrated that tacrolimus increases HEV infection in hepatic cells, whereas MMF suppresses HEV proliferation.
Poor T cell response to HEV also plays a role in HEV reinfection.
In conclusion, this report illustrates that anti-HEV IgG may not be protective in immunosuppressed patients. Suspected cases should undergo HEV NAT testing,
dietary counseling regarding consumption of raw or undercooked meat (pig) is crucial, and HEV reinfection can be successfully treated with ribavirin.
Chronic hepatitis E after kidney transplantation with antibody response suggestive of reinfection: a case report
A 64-year-old
The primary disease for his ESRD was FSGS
Kidney transplantation April 2016
Recurrent FSGS post-transplant (June 2016) treated with: Rituximab, TPE x 26 times
Complicated with BK viremia
Presented with worsening derangement of liver enzyme
HCV RNA negative
HEV RT-PCR detected (since > six months earlier) – before the transplant was negative (IgM negative) with positive IgG
anti-HEV IgM detected
anti-HEV IgG detected
Treatment with Ribavarin 200 mg 5 times a day for 11 weeks
Outcome: Negative HEV RNA and normalisation of liver enzyme
Conclusion: anti-HEV did not confer protection in this patient; perhaps it is related to the number of antibodies.This is partly contributed by anti-CD20 therapy.
CHRONIC HEP E AFTER KIDNEY TRANSPLANTATION WITH AN ANTIBODY RESPONSE SUGGESTIVE OF REINFECTION;A CASE REPORT.
BACKGROUND
HEV prevalence estimated at <1% to 52 % in Europe. Although HEV antibodies are expected to be protective, we are yet to get threshold levels for protection. This case is on a pt with chronic HEV post transplant despite high initial antibody levels.
CASE PRESENTATION.
64 yr old ESRD from FSGS,KTR in 2016,meds;tac,MMF and PDL,2/12 later he got PLEX(26 times) with albumin and FFP due to recurrent FSGS.
3/12 post transplant, BKV viremia detected, PDL and MMF tapered down and later MMF was reinstated to pre treatment levels.4/12 later, IVIG given for hypoalbuminamia.8/12 post transplant he had elevated transaminases but with a normal liver ultrasound.9/12 post transplant, he still had elevated transaminases but with better AST and ALT with again a normal rpt ultrasound. HCV was negative but HEV RNA was +VE, anti HEV IgM and IgG were equally +VE. Retrospective studies showed +VE HEV over last 7/12.Samples pre transplant too were +VE anti HEV IgG and neg for anti HEV IgM and HEV RNA.
17/12 post transplant he had ribavirin tx for 11 weeks until he got anemic. HEV RNA was neg 18/12 post transplant and remained +VE indicating successful tx. LFTS normalized. Pt mode of HEV acquisition was not clear.
DISCUSSION AND CONCLUSION.
In our pt, HEV antibodies were not protective against chronic HEV.WHO proposes minimum antibody levels of 2.5 units/ml to be protective. This is not yet agreed across board to be applied clinically post transplant.
Take home points;
Anti HEV IgG is not protective and thus should not be routinely done at the beginning of immunosuppression.
Before beginning immunosuppression, LFTS and HEV infection should be tested once LFTS are noted to be rising.
HEV infection diagnosis with nucleic acid testing should be done in immunosuppressed.
Thorough counselling on HEV infection post transplant should be done.
Humoral and T cell mediated immunity role in HEV reinfection is not clear and needs further studies
·HEV infection is a major cause of acute hepatitis worldwide, with five human pathogenic genotypes known.
·HEV genotype 3 (gt3) is the dominant genotype in Europe, with seroprevalence rates ranging from < 1% up to 52%.
·In general, HEV infection remains asymptomatic or self-limiting, but in immunosuppressed patients, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates.
·This study reports a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG pre- and post-transplantation and describes and characterizes the HEV-specific antibody response over time.
Method:
·This case study describes a patient with immunosuppression who contracted persistent HEV infection despite having high levels of antibodies.
·Due to elevated liver enzymes, HEV infection was discovered using RT-PCR after the diagnostic examination.
·Retrospective examination of serum samples that had been preserved revealed that the patient had been HEV RNA positive for 7 months.
·Ribavirin was used to successfully treat a chronic HEV infection.
Discussion and conclusions
·HEV infection despite detectable anti-HEV IgG before and after kidney transplantation, suggesting HEV reinfection.
·Immunocompromised individuals with low anti-HEV IgG levels are not protected against reinfection.
·While anti-HEV IgG levels did not decrease below the cut-off due to rituximab-induced B cell depletion, this suggests that functioning B cells are not the main correlate of protection.
·The epitope-specific analysis of the immune response showed antibodies directed against ORF2, paralleled by an increase in anti-HEV IgG.
·Immunosuppressive therapies may influence the humoral immune response and HEV replication cycle, as demonstrated by Wang and colleagues.
·Chronic HEV infection has been associated with an impaired HEV-specific T-cell response, which needs further study.
·We did not detect HEV RNA before and shortly after transplantation, suggesting no reactivation.
·Ribavirin is the only drug available for HEV infection, but novel treatment strategies are needed, such as sofosbuvir and interferon alfa.
·Testing for anti-HEV IgG before immunosuppression and counseling patients at risk for chronic HEV infection is important for clinical practice..
Conclusion:
·In addition to demonstrating the value of RT-PCR for HEV diagnoses in immunocompromised individuals, this example demonstrates that HEV antibodies do not provide complete protection from HEV infection.
·It would appear prudent to counsel individuals who are susceptible to persistent HEV infection.
·More research is needed to understand the function of the humoral and T-cell-mediated immune response in HEV reinfection patients.
This is a case report of A 64-year-old man, had kidney transplantation in April 2016. He is maintained on tacrolimus, mycophenolate mofetil and prednisone. In addition, he received rituximab twice and therapeutic plasma exchange (26 times), due to recurrence of focal segmental glomerulosclerosis. His post-transplantation course showed BKV viremia that was treated with reduced immune suppression and Igs.
in November 2016, routine laboratory testing revealed elevated AST, ALT and γ-GT (276 U/ L. Ultrasound of the liver was normal.
Testing for hepatitis C virus RNA was negative, however, HEV RNA was detected using RT-PCR. Concomitantly anti-HEV IgM (71.5 AU/mL) and IgG (149 AU/mL) using ELISA were positive. Retrospective analysis of stored plasma samples showed positive HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection. analysis of HEV RNA demonstrated an HEV genotype 3c. Interestingly, stored plasma samples taken before kidney transplantation were positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before transplantation.
To better appreciate the level of HEV IgG antibodies, a quantitative HEV ELISA was used, which was calibrated against the WHO standard and expresses HEV IgG in IU/ml. Early samples tested HEV IgG borderline (April 2016) and negative (August 2016).
Patient was started treatment with ribavirin (200 mg, 5 doses daily), for 11- weeks course and therapy was stopped due to anemia. HEV RNA in plasma was first negative in October 2017 and remained negative indicating successful therapy. Liver enzymes returned back to normal range.
Since earlier samples were negative, the mode of acquisition of HEV infection in this patient remains unclear but could be related to HEV contaminated blood products, an HEV-contaminated transplant organ, or food uptake after transplantation. Furthermore, the rituximab induced B cell depletion might have influenced the development of HEV antibodies in this patient, but anti-HEV IgG levels did never fall below the cut-off of the assay. Thus, impaired B cells in our immunosuppressed patient might have contributed to reinfection despite the presence of HEV antibodies.
Though this patient had detectable anti-HEV IgG before and after kidney transplantation, yet HEV reinfection had occur and indicates that HEV antibodies did not confer protection in this patient.
Of note, in immunocompromised patients a French study found that a low anti-HEV IgG of < 7 WHO units/mL did not protect against reinfection.
Treatment with ribavirin was successful in this patient but anemia as well-known side effect of ribavirin led to the discontinuation of antiviral therapy. Currently, ribavirin is the only drug available for treatment of HEV infection. Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
For clinical practice the following points remain important:
I. The presence of anti-HEV IgG may not be protective.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
Summary
HEV seroprevalence rates ranging from < 1% up to 52% in Europe. HEV gt3 is transmitted zoonotically to humans and infections are linked to the consumption of HEV contaminated meat products. The humoral immune response begins with the rise of anti-HEV IgM antibodies followed by the development of a robust anti HEV IgG response. The anti-HEV IgG antibody concentration then slowly declines over time but may remain detectable for years. In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates.
Here, in this case report a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG pre- and post-transplantation.
In this case study a 64-year gentleman underwent kidney transplantation in April 2016, end stage kidney disease was secondary to focal segmental glomerulosclerosis. Immunosuppressive medication included tacrolimus, mycophenolate mofetil and prednisone. In addition, he received rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma. He has BK viremia treated by reduction of immunosuppressive medications (MMF), and Intravenous immunoglobulins (10 g) were given on June 2016 due to hypogammaglobulinemia. In November 2016, found to have modest elevation of liver function ALT 81, AST and gamma GT 276.HEV RNA was detected using RT-PCR. Concomitantly anti-HEV IgM and IgG using ELISA were positive.
Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection.
Discussion
Choi and coworkers demonstrated that rhesus macaques with low HEV-IgG titers (< 6 IU/ml) were not protected against HEV reinfection. Despite the rapid anti-HEV IgG response this did not lead to clearance of HEV RNA from the blood in our patient.
The rituximab induced B cell depletion might have influenced the development of HEV antibodies in this patient but in this case anti-HEV IgG levels did never fall below the cut-off of the assay.
Impaired B cells in our immunosuppressed patient might have contributed to reinfection despite the presence of HEV antibodies.
Beyond the humoral response and the immunosuppressive therapy chronic HEV infection has been associated with an impaired HEV-specific T-cell response in transplant patients
At the moment ribavirin is the only drug available for treatment of HEV infection and new treatment strategies are urgently needed. Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
Conclusion
In this HEV reinfection case, who developed a chronic course which was successfully treated with ribavirin in spite of having HEV Igg. The role of the humoral and T-cell mediated immune response in cases of HEV reinfection is inconclusive and needs further study.
Summarise this article Background
-Hepatitis E virus (HEV) infection is increasingly recognized
as a major cause of acute hepatitis worldwide. HEV genotype 3 (gt3) is the dominant HEV genotype in Europe.
-HEV gt3 is transmitted zoonotically to humans and infections
are linked to the consumption of HEV contaminated meat
products.
-It remains asymptomatic or presents as mild and self-limiting disease. -The humoral immune response begins with the rise of anti-HEV IgM
antibodies followed by the development of a robust anti- HEV IgG response . Case report
-A 64-year-old man with a history of focal segmental glomerulosclerosis
underwent kidney transplantation in April 2016 on tacrolimus, mycophenolate mofetil and prednisone. His post-transplantation course showed BKV viraemia ,elevated liver enzymes chronic HEV infection. – This suggests HEVreinfection and indicates that HEV antibodies did notconfer protection in this patient.
-Impaired B cells in our immunosuppressed patient might have contributed to reinfection despite the presence of HEV antibodies.
– Anti-HEV IgG titers decreased shortly after transplantation suggestion an influence of the immunosuppressive therapy on the humoral immune response.
-Immunosuppressive therapies might interfere with the HEV replication cycle . Tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication
and steroids showed no effect at all .
-This patient developed chronic HEV infection which can lead to rapidly developing cirrhosis and liver failure . Ribavirin is the only drug available for treatment of HEV infection and novel treatment
strategies are urgently needed. For clinical practice the following points remain important:
I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti- HEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before
immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
HEV infection remains asymptomatic or presents as mild and self-limiting diseaseز Of note, no definitive minimum protective HEV antibody concentration has been established yet.
In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality rates.
This article presented a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation. This suggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient
Currently, ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently needed. Pegylated interferon- alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report Background :
HEV infection is a major cause of acute hepatitis worldwide, with five human pathogenic genotypes known. HEV genotype 3 (gt3) is the dominant genotype in Europe . The humoral immune response begins with the rise of anti-HEV IgM antibodies followed by the development of a robust anti HEV IgG response. In immunosuppressed patients, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates, but the HEV specific antibody response is variable or lacking at large.
case report :
A 64-year-old man with a history of focal segmental glomerulosclerosis underwent kidney transplantation in April 2016. After transplantation his immunosuppressive regimen included tacrolimus, mycophenolate mofetil and prednisone he was given rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as replacement fluid for recurrent FSGS . His post-transplantation course showed BKV viremia Three months after transplantation he developed BKV viremia for which reduction of immunosuppression was done . Ultrasound of the liver done 6 months after transplantation because of high liver enzymes which showed no pathological findings .other screening of HBV,HCV were negative . HEV RNA was found to be positive in retrospective samples over the last 7 months which is consistent with chronic HEV infection. Anti-HEV IgG showed a rapid rise after HEV RNA was first detectable in September 2016 and became positive in February 2017. The patient received an 11-week course of ribavirin (off-label use) and therapy was stopped due to anemia. HEV RNA in plasma was negative in October 2017 and remained negative indicating successful therapy. The mode of transmission of HEV infection was unclear in this patient, he had no recent travel and no information on food consumption was possible
Discussion :
This study showed a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation. HEV antibodies are considered to be pivotal to control the infection, and a minimum protective antibody concentration of 2.5 World Health Organization (WHO) units/mL has been proposed. Despite the rapid anti-heV IgG response, this did not lead to clearance of HEV RNA from the blood in the patient, suggesting a limited protective humoral response. Immunosuppressive therapies may also interfere with the HEV replication cycle. The CD8+ Tcell response in chronic HEV patients was diminished in comparison to the acute disease course, but was partially restored after ribavirin therapy which is the only available treatment so urgent novel treatment strategies are needed . Conclusion :
HEV infection should be suspected for any unexplained elevated liver enzymes in immunosuppressed patients . , diagnosing HEV infection using nucleic acid testing, counseling patients at risk for chronic HEV infection regarding the consumption of raw/undercooked pig products. The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
Introduction
HEV recently consider the most common cause of acute hepatitis worldwide with good immune response and self-limiting viral infection without treatment however in immunosuppressed patients there is growing evidence supporting the reactivation of HEV and causes chronic HEV infection with fast progression to liver cirrhosis up to 10%. If left untreated, there are 5 genotypes of HEV genotype 3 is more predominant in Europe with quite variable prevalence from < 1 to more > than 50% in some parts. HEV genotype 3 (gt3) is mainly transmitted through the ingestion of contaminated raw animal meat from pigs. Can be asymptomatic but there is an increased risk of reactivation after SOT and progress to chronic HEV infection with the only clue being the unexplained elevated liver enzymes despite adequate HEV IgG level. this case report of Chronic hepatitis E after kidney transplantation despite good antibody response suggestive of reinfection indicates that HEV antibodies did not confer protection in this patient and addresses the importance of RT-PCR molecular testing for the diagnosis of HEV infection and emphasizes that HEV antibodies alone are not protective against reactivation of HEV in immunocompromised patients after SOT
No clear cut-off value of anti-HEV IgG level to be considered protective however some studies suggest value < 7 IU is not protective against HEV reactivation or reinfection in general the
The mode of transmission of HEV is either through blood and blood product contamination or through transplant organ contamination, and ingestion of raw contaminated meat.
Impaired B cells with rituximab might have contributed to reinfection despite the presence of HEV antibodies. Immunosuppression therapy after SOT as reported by one study that tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect at all.
Currently, ribavirin is the only drug available for the treatment of HEV infection with the risk of hemolytic anemia, novel treatment is needed so far alternatives like sobovivor in resistance cases have been studied
Take home message from this case report
HEV re-infection or reactivation should be considered after SOT with persistent unexplained elevated liver enzymes
HEV IgG antibodies level is of limited value in the diagnosis and protection against HEV reinfection. and we need HEV RNA (NAT) In immunosuppressed patients, for confirmation of the diagnosis
Education of the patients with proper counseling about the avoidance of raw meat or undercooked pig products.
After reviewing this case report i just asked our gastero-team about the epidemiology of HEV in our region and whats our practice about the screen , in our center we do HEVserologyy only and we don’t have HEV RNA as it’s under the request of exterinalitemm
This is a case report of re-infection of Hepatitis E virus which did not resolve spontaneously post transplant and became chronic
Introduction:
HEV is becoming one of the common causes of hepatitis. The seroprevalence of HEV in Europe ranges from less than 1% to 52%. There are 5 genotypes with genotype 3 being the most common in Europe. It is transmitted by consuming contaminated meat. Normally HEV infection is asymptomatic and self limiting but can result in fulminant hepatitis in pregnant women. The humoral immune response manages the infection with a rise in IgM followed by IgG but the IgG titers wane over time. In the immunocompromised patient, the clearance of the virus is affected and can lead to chronicity
Case presentation
A 64 year old male with ESKD secondary to FSGS who underwent kidney transplant in April 2016 and was on triple immunosuppression with tacrolimus, MMF and prednisone. He received plasma exchange and rituximab post transplant due to recurrence of FSGS. He also received IVIG due to hypogamaglobulinemia. On routine liver function test, he was found to have elevated transaminases with a normal liver USS. Further investigations revealed HEV infection. Both HEV IgM and IgG titers were high. retrospective analysis of serum samples from September 2016 showed the presence of HEV RNA. Genotyping revealed it to be genotype 3c. The stored plasma pre-transplantation showed elevated titers of IgG and no titers of IgM and no detectable HEV RNA suggesting prior HEV infection. he was started on ribavirin 200 mg five times daily for 11 weeks. the treatment was stopped due to the development of anemia.
Discussion
This case shows re-infection with HEV with no protection conferred by the IgG Ab. HEV Ab are considered vital to prevent re-infection. Recently HEV Ab have been standardized and a minimum protective Ab concentration of 2.5 WHO units/ml have been proposed. However, a definitive protective titer has not been conclusively assessed as yet. The patient had a rapid rise in the anti HEV IgG titers followed by a rise in the anti HEV IgM titers indicating a booster response. However, it was not sufficient to clear the virus. The impaired B cells due to immunosuppression could have been responsible for the lack of clearance. The anti-HEV IgG titers decreased shortly post-transplantation suggesting an influence of immunosuppression on the humoral response. Wang et al have shown that tacrolimus promoted the infection of liver cells by HEV whereas MMF inhibited HEV replication.
Currently ribavirin is the only drug available for the treatment of HEV infection. Pegylated interferon alpha has activity against HEV but cannot be used in HSCT or SOT as it can trigger rejection
It is important to note that anti-HEV IgG may not be protective against HEV especially post transplant due to immunosuppression and clinical work up of transaminitis should include HEV RNA. Patients undergoing transplant should be advised against eating raw or undercooked meat
HEV virus is an important cause of hepatitis before and after transplantation.
The case showed a patient with HEV infection despite the prescene of high anti HEV antibodies.
Treatment of HEV infection with ribavirin is good option .
Anti HEV antiboies may not be protective of reinfection prior to transplantation.
Introduction: – Hepatitis E virus (HEV) infection is an important reason for acute hepatitis with increasing prevalence worldwide. – HEV specific antibodies are developed after acute infection and thought to confer protection against re-infection. – HEV gt3 can progress to a chronic infection with high morbidity and mortality in immunocompromised.
Case presentation: – A 64-year-old man transplanted on April 2016 for FSGS and maintained on triple immunosuppression therapy. – 2 months post-Tx, he had FSGS recurrence and treated with RTX, PLEX (26 times). – 6 months post- Tx, he developed BKPyV viremia, treated with IS reduction and IVIG. – November 2016, routine testing revealed elevated transaminases ( dropped after month) and GGT with normal US. – March 2017, diagnosed with active HEV infection positive anti-HEV IgM & IgG. – Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection – Stored pre-transplant sample tested and it indicated resolved HEV infection before KT (positive anti-HEV IgG, negative IgM & HEV RNA). – In September 2017, treated with ribavirin for 11 weeks , stopped for anemia. – October 2017, HEV RNA negative and liver enzymes normalized indicated successful therapy. Discussion: -Chronic HEV infection can develop despite the presence of anti-HEV IgG. -This indicates that HEV antibodies did not confer protection in this patient. – The definitive protective antibodies titer has not been firmly assessed yet. – HEV serological assays differ in their performance and standardization of antibody assays is under debate. – Immunosuppressive therapy influence humoral immune response which affect antibodies titer, and caused impaired HEV-specific T-cell response Conclusion:
-Anti-HEV IgG may not be protective, its value of testing is limited.
– Testing for HEV infection in patients with elevated liver enzymes.
– The diagnosis of HEV infection in immunosuppressed patients by NAT.
– Counseling for the risk of HEV infection if raw/ undercooked pig products is consumed.
– Further study is needed for the role of the humoral and T-cell immunity in HEV.
This is a case report of a renal transplantation patients with HEV reinfection who developed chronic HEV despite having a pre-transplantation formed HEV antibodies. HEV infection was detected using RT-PCR upon diagnostic evaluation due to increased liver enzymes. Upon retrospective analysis of stored serum samples, it was found that the patient was HEV RNA positive since 7 months.
Chronic HEV infection was successfully treated with ribavirin 200 mg 5 times daily for 11 weeks then stopped because of the anemia.
The exact mode of transmission was unclear as the patient did not receive blood transfusion or travelled abroad.
Important clinical lessons:
1- The presence of anti-HEV IgG may not be protective thus limiting the value of testing
for anti- HEV IgG before the start of immunosuppressive regimens. no determined
definite cut off value for the protective HEV antibody level.
2- Clinical work-up upon increased liver enzymes should include testing for HEV
infection irrespective of the anti-HEV IgG status before immunosuppression.
3- Counseling patients at risk for chronic HEV infection regarding the consumption of
raw/ undercooked pig products seems advisable.
4- The role of the humoral and T-cell mediated immune response in cases of HEV
reinfection deserves further study.
☆Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
__________________________________
◇ Background
▪︎Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
▪︎To date, five human pathogenic HEV genotypes are known.The dominant one in Europe is genotype 3 (gt3), which is transmitted zoonotically to humans.
▪︎HEV infection remains asymptomatic or presents as mild and self-limiting disease.
▪︎The humoral immune response begins with the rise of anti-HEV IgM Abs, followed by the development of a robust antiHEV IgG response.
▪︎The anti-HEV IgG antibody concentration then slowly declines over time but may remain detectable for years.
▪︎In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates. In these patients the HEV specific antibody response is variable or lacking at large. _________________ ◇ Case presentation: ▪︎The authors reported an immunocompromised patient who developed chronic HEV infection despite the presence of high level antibodies. ▪︎HEV infection was detected using RT-PCR upon diagnostic evaluation due to increased liver enzymes. ▪︎Upon retrospective analysis of stored serum samples the authors have found that the patient was HEV RNA positive since 7 months. Chronic HEV infection was successfully treated with ribavirin.
◇ For clinical practice the following points remain important: I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressive regimens. II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression. III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing. IV. Counsel patients at risk for chronic HEV infection. V. The ability to identify patients with HEV reinfection who developed a chronic course which was successfully treated with ribavirin. The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
◇ Conclusion ▪︎This case reported a patient who suffered from a chronic course of HEV infection, which was successfully treated with ribavirin. ▪︎ It underlines the importance of RT-PCR for HEV diagnostics in immunosuppressed patients and supports the notion that HEV antibodies do not confer universal protection. ▪︎Counseling patients at risk for chronic HEV infection seems advisable. ▪︎The role of the humoral and T-cell mediated immune response in cases of HEV reinfection needs further study
Background
The zoonotic transmission of acute hepatitis caused by the hepatitis E virus (HEV) and its five genotypes through infected meat products, particularly genotype 3 in Europe, typically results in a mild, self-limiting sickness. IgM and IgG antibodies against HEV are part of the humoral immune response, and these antibodies may be detectable for years. Acute HEV gt3 infection can proceed to a chronic course in immunosuppressed patients, which can result in substantial morbidity and mortality. Despite having high levels of anti-HEV IgG antibodies, the case study reveals the development of chronic HEV infection.
Case presentation
A 64-year-old man with focal segmental glomerulosclerosis (FSGS) on tacrolimus-based triple drug immunosuppression, a history of treatment for FSGS recurrence (plasmapheresis and rituximab), and BK viremia experienced elevated liver enzymes (AST, ALT, and GGT) in November 2016 despite the absence of any clinical symptoms. Despite AST and ALT returning to normal in March 2017, GGT remained high. On inquiry, HEV RNA PCR, anti-HEV IgM, and anti-HEV IgG were positive. HEV genotype 3c was the type. Retrospective blood sample analysis found positive HEV RNA in a sample taken in September 2016 and positive anti-HEV IgG with negative anti-HEV IgM and HEV RNA in a sample taken before the transplant. Anti-HEV IgM levels increased concurrently with a sharp rise in anti-HEV IgG up until February 2017. In September 2017, the patient underwent an 11-week course of ribavirin treatment before the treatment was stopped due to anemia. In October 2017, liver enzymes returned to normal and plasma HEV RNA became negative.
Discussion
The instance described demonstrates that anti-HEV antibodies do not provide protection against HEV reinfection. A minimal protective threshold of 2.5 WHO units/mL for anti-HIV antibodies has been proposed. Anti-HEV IgG titres below 6 IU/mL (or 7 WHO units/mL) have been proven to not protect against HEV reinfection. Anti-HEV antibodies in the index patient were 7 IU/ml and were therefore not protective. The use of rituximab resulted in B cell reduction, which ultimately led to reinfection despite the presence of anti-HEV antibodies. Anti-HEV antibodies decreased post-transplant (due to immunosuppressive drugs), compromising the ability to prevent HEV reinfection. It has been demonstrated that tacrolimus increases HEV infection of hepatic cells, whereas MMF suppresses HEV proliferation. Poor T cell response to HEV also plays a role in HEV reinfection.
In conclusion, this report illustrates that anti-HEV IgG may not be protective, elevated liver enzymes would call for HEV infection testing, immunosuppressed patients should undergo HEV NAT testing, patient dietary counseling regarding consumption of raw or undercooked meat (pig) is crucial, and HEV reinfection can be successfully treated with ribavirin.
IV. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report Summarize this article.
This article reports a case of chronic HEV infection that occurred shortly after KTX despite the presence of high titer of anti-HEV IgG pre- & post-TX.
Hepatitis E virus (HEV) infection
Is a major cause of acute hepatitis.
Five human pathogenic genotypes are recognized.
Genotype 3 is the dominant one in Europe (seroprevalence
rates < 1% up to 52%).
Transmission:
Zoonotic (from consumption of HEV contaminated meat products).
Presentation:
Asymptomatic
Mild & self-limiting disease.
The initial rise of anti-HEV IgM antibodies is followed by a robust anti-HEV IgG response that wanes slowly over time but may remain detectable for years.
It is controversial whether this antibody response will confer protection against re-infection.
In immunosuppressed patients, acute infection can progress to chronicity (HEV RNA detectable > 6 months) with high morbidity & mortality rates.
WHO has, recently, standardized a minimum protective antibody concentration of 2.5 (a definitive protective titer is lacking).
Clinical practice points:
Anti-HEV IgG may not be protective. This limits the value of testing for anti- HEV IgG before the start of IS regimens.
Testing for HEV infection should be included in the workup of any increased liver enzymes irrespective of the anti-HEV IgG status before immunosuppression.
NAT should be used for diagnosis In immunosuppressed patients.
Counsel at risk patients about the role of the consumption of raw/undercooked pig products.
Chronic HEV course developing after recurrent infection can successfully be treated using ribavirin.
The role of the humoral & T-cell mediated immune response in cases of HEV re-infection needs further study.
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report. Background.
HEV is considered one of the most common cause of acute hepatitis, especially HEV genotype 3 (gt3) is the dominant HEV genotype and after infection HEV IgG rising but slowly declines over time, and reported re-infection of HEV in some immunocompromised cases despite the presence of detectable anti-HEV IgG before.
This article present a post kidney transplant case complicated with HEV re-infection and its response to Ribavirin, that highlight the role of immunosuppression on humoral and T-cell mediated immune response. Added some clinical advices such as:
=Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
=In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
=Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable. Conclusion:
The possibility of HEV re-infection is still standing despite the presence of detectable anti-HEV IgG before and there is no a definitive protective titer has not been firmly assessed yet in immunocompromised patients and should be treated by Ribavirin.
Summary Background
HEV recognised as a major cause of hepatitis worldwide.
There are 5 genotypes, genotype 3 dominant in Europe and transmitted though consumption of contaminated meat.
General population causes a mild self limiting disease, however in immunosuppressed infection may progress to chronic infection.
The case
64 year old with FSGS transplanted in 2016 and initiated on triple maintenance immunosuppressive therapy.
Post transplant complications:
June 2016 received rituximab and plasma exchange due to recurrence of FSGS.
3 months after transplant had BKV viremia necessitating tapering of MMF.
June 2016 had hypogammaglobulinemia necessitating immunoglobulin infusion.
October 2016 deranged liver enzymes with normal liver U/S
March 2017 deranged GGT with normal AST and ALT, liver U/S normal.
Hepatitis C negative
HEV RNA positive.
Retrospectively noted to be positive since September 2016.
Pre-transplant was positive for IgG anti-HEV and negative for IgM anti -HEV and HEV RNA- indicating prior infection however ? occult infection.
September 2017 initiated treatment with ribavirin.
October 2017 HEV RNA negative and remained so.
Discussion.
HEV antibodies are pivot to control infection, however a titer that confers protection has not been defined.
Impaired B cells in this patient who had received rituximab may have contributed to reinfection despite the fact that the patient had HEV antibodies.
IgG anti-HEV titers decreased shortly after transplant due to the immunosuppressive therapy.
Ribavarin is the only current treatment available for HEV.
Pegylated interferon has some activity against HEV however can’t be used in SOT due to risk of rejection.
Conclusion
IgG anti-HEV may not be protective.
Elevated liver enzymes warrants testing for HEV infection irrespective of anti-HEV status prior to transplant.
HEV infection in transplant recipient should be diagnosed with nucleic acid amplification test.
Patients should be counselled on the infection from consumption of raw/undercooked infected meat.
Role of humoral and T cell mediated immune response in HEV infection requires further study.
Background: Hepatitis E Virus (HEV) with its 5 genotypes is responsible for acute hepatitis worldwide (especially genotype 3, gt3 in Europe) through zoonotic transmission via contaminated meat products culminating in mild, self-limiting disease usually. Humoral immune response includes IgM antibodies followed by IgG antibodies against HEV which may remain detectable for years. In immunosuppressed patients, acute HEV gt3 infection can progress to chronic course leading to high morbidity and mortality. The case presented shows development of chronic HEV infection despite presence of high anti-HEV IgG antibodies.
Case Presentation: A 64-year-old renal transplant recipient (April 2016), with basic disease of focal segmental glomerulosclerosis (FSGS), on tacrolimus based triple drug immunosuppression, and history of treatment for FSGS recurrence (Plasmapheresis and rituximab) as well as BK viremia developed elevated liver enzymes (AST, ALT, GGT) in November 2016 in absence of any clinical symptoms. GGT was still elevated in March 2017, although AST and ALT normalized. On investigation, HEV RNA PCR, anti-HEV IgM and anti-HEV IgG were positive. The genotype was HEV genotype 3c. Retrospective analysis of stored blood samples revealed positive HEV RNA in September 2016 sample and positive anti-HEV IgG with negative anti-HEV IgM and HEV RNA in the pre-transplant blood sample. The anti-HEV IgG rapidly rose upto February 2017, and then fell, with concomitant rise in anti-HEV IgM. Patient was treated with ribavirin in September 2017 for 11 weeks, with cessation of therapy due to anemia. Plasma HEV RNA became negative in October 2017 and liver enzymes became normalized.
Discussion: The presented case illustrates the fact that anti-HEV antibodies do not confer protection from HEV reinfection. A value of 2.5 WHO unit/ml anti-HEV antibodies has been proposed as the minimum protective value. It has been shown that anti-HEV IgG titres less than 6 IU/ml (or <7 WHO unit/ml) do not protect against HEV reinfection. The index patient’s anti-HEV antibodies were <7 IU/ml, and were hence non-protective. The use rituximab led to B cell depletion, causing loss of functional B cell ultimately leading to reinfection despite anti-HEV antibodies. Anti-HEV antibodies reduced post-transplant (due to immunosuppressive medications), affecting the ability to counter HEV re-infection. Tacrolimus has been shown to increase HEV infection of hepatic cells while MMF inhibits HEV proliferation. Impaired HEV specific T cell response also has role in HEV reinfection.
Conclusion: The case highlights that anti-HEV IgG may not be protective, elevated liver enzymes would warrant HEV infection testing, HEV NAT testing should be done I immunosuppressed patients, patient dietary counselling regarding raw/undercooked meat (pig) consumption is very important, and HEV reinfection can be treated successfully with ribavirin.
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
Summary:
· Although HEV is a major cause of acute hepatitis worldwide with acquired lifelong protection, it was reported to have a chronic course of HEV infection.
· The case had KT due to ESKD 2ry to FSGS and was maintained on tac based triple IS therapy.
· Testing for HEV RNA was requested due to elevated liver enzymes.
· Diagnosis of chronic infection was made as PCR was positive in stored sample withdrawn 7 months before this time.
· Ribavirin was used for treatment.
· RT-PCR is the standard for diagnosis in immunosuppressed patients.
· There is a notion that HEV antibodies do not confer universal protection, as this case has positive PCR in spite of positive antibodies in the serum.
· Counseling patients about risk of chronic HEV infection is advisable and better avoidance of undercooked pork meat.
· The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study
April 2016
A 64-year-old man
FSGS underwent RTX
TAC- MMF- PRED.
June 2016
rituximab and PE (26 times) with albumin and fresh frozen plasma (recurrence of FSGS), resolved until October 2016.
BKV viremia three months after transplantation.
Prednisone was tapered and MMF was reduced. BKV viremia remained below 1000 copies/mL plasma from October 2016 onwards and mycophenolate mofetil was increased.
IVIG were given once at the end of June 2016 due to hypogammaglobulinemia.
November 2016,
elevated AST , ALT and γ-GT .
March 2017,
1- increased γ-GT but AST and ALT normal
US was normal.
2- Testing for hepatitis C virus RNA was negative
3- HEV RNA was detected using RT PCR indicating active HEV infection.
4- anti-HEV IgM and IgG using ELISA were positive.
Retrospective analysis of stored plasma samples showed ;
1- stored plasma samples taken before kidney transplantation
anti-HEV IgG positive
anti-HEV IgM negative
HEV RNA resolved HEV infection before transplantation
2- in September 2016
Anti-HEV IgG : a rapid rise
HEV RNA : first detectable
anti-HEV IgM : negative
3- in February 2017
anti-HEV IgM became positive
detection of anti-HEV IgG antibodies directed against the C terminal end of the ORF2 protein (O2CGt1 and O2CGt3) whereas antibodies against the middle and the N-terminal end of ORF2 were not detectable
4- In September 2017,
treatment with ribavirin was initiated.
He received an 11week course of ribavirin (off-label use) and therapy was stopped due to anemia.
5 – in October 2017
HEV RNA in plasma: was first negative and remained negative indicating successful therapy.
Liver enzymes returned back to normal range.
Discussion and conclusions
1- It is a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation.
Reinfection indicates that HEV antibodies did not confer protection in this patient.
2- HEV antibodies have been standardized concentration of 2.5 (WHO) units/mL.
However, a definitive protective titer has not been firmly assessed yet.
Choi and coworkers demonstrated that low HEV-IgG titers (<6IU/ml) were not protected against HE reinfection
French study found that a low anti HEVIgG of<7 WHO units/mL did not protect against reinfection
In this patient , despite the rapid anti-HEV IgG response this did not lead to clearance of HEV RNA from the blood in our patient.
This supports the notion of a limited protective humoral immune response.
Wang and colleagues showed that tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect at all
3- the rituximab induced B cell depletion might have influenced the development of reinfection despite the presence of HEV antibodies.
4- the T-cell mediated immune response remains largely unclear in HEV infection and deserves further study.
Treatment
1- ribavirin was successful in this patient but anemia as well-known side effect
2- Currently, ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently needed.
3- Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
For clinical practice the following points remain important:
I. The presence of anti-HEV IgG may not be protective
II- Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection seems advisable.
In conclusion,
1- we were able to identify a patient with HEV reinfection who developed a chronic course which was successfully treated with ribavirin.
2- The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
I make note of your interpretation of serological and molecular testing reports pertaining to Hep E infections in relation to timings in the natural history. I like your summary.
Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
There are 5 HEV genotypes , HEV genotype 3 (gt3) is the common and dominant in Europe.it transmitted from animal to human .
HEV generally a symptomatic or presenting as mild disease and self- limiting disease.
The humoral immune response begins with the rise of anti-HEV IgM antibodies followed by the development of antiHEV IgG response .
The anti-HEV IgG antibody concentration then slowly declines over time but may remain detectable for years.
Acute HEV gt3 infection In immunosuppressed patients can progress to a chronic course which increase morbidity and mortality rates. Case presentation
A 64-year-old man with a history of focal segmental glomerulosclerosis underwent kidney transplantation in April 2016. Immunosuppressive medication was tacrolimus ,MMF and prednisone. he received rituximab 750 mg twice and plasma exchange (26 times) with albumin and fresh frozen plasma.
Three month post transplantation affected by BKV viremia and hypogammaglobulinemia,Immune suppressions was reduced till infection released then initial dose stated again .
Seven month post transplantation discover during routine he had high ALT and γ-GT with normal liver US ,4 month after γ-GT still high but AST and ALT were normal .
Investigations was
1. HCV RNA was negative
2. HEV by PCR was positive.
3. anti-HEV IgM and IgG by ELISA were positive.
4. HEV RNA over the last 7months was detected (from stored plasma).
5. anti-HEV IgG positive and anti-HEV IgM negative (from stored plasma).
After six month, treatment started with ribavirin 200 mg in five dose daily ,his liver enzymes still high (AST (77U/ L), ALT (78U/L), and γ-GT (226U/L)
Ribavirin continue for 11 weeks but stopped due to anemia .
HEV RNA become negative and liver enzyme return to normal . Discussion
HEV reinfection leading to chronic cource.
Critically, they only analyzed a limited number of animals infected with HEVgenotype1.
low anti-HEV IgG of <7 WHO units/mL did not protect against reinfection.
The presence of anti-HEV IgG may not beprotective.
Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
conclusion,
we were able to identify a patient with HEV reinfection who developed a chronic course which was successfully treated with ribavirin.
The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
5 genotypes exists, genotype 3 is the most common genotype in Europe
The main route of transmission is through ingestion of undercooked meat
Clinically it is usually self-limited disease, but is significant in transplantation
After infection, IgM start to rise, then IgG start to appear later on and persist for long period, then wan gradually
Some recommend that the Appearance of IgG give lifelong immunity but this is debatable since cases of recurrent HEV has been reported
The current case study presents 64 years old male who underwent renal transplantation due to ESRD related to FSGS, he was on triple immunosuppression, received plasmapharesis and Rituximab for recurrent FSGS 2 months after transplantation with favorable outcome
BK virema detected with subsequent reduction of immunosuppression, and stabilization of BK load< 1000 copis /ml
After 7 months of transplantation, liver enzymes was mildly elevated and HEV PCR, HEV IgM, and IgG were positive
On looking at stored sample at the time of transplantation, the sample was also positive for HEV, HEV IgM, and IgG indicating chronic HEV infection (> 6 months)
9 months later, treatment started in the form of ribavirin 1000 mg daily for 11 weeks, stopped due to side effects (anaemia), clearance of the virus occur after 2 months of treatment, remain negative and enzymes normalized
Conclusion
Chronic HEV infection should be considered in renal transplant recipient with hepatic dysfunction
The presence of IgG is not protective and reactivation can occur in the presence of IgG Ab
The use of Rituximab and tacrolimus may be associated with high risk of HEV infection, MMF may be associated with lower risk and steroid is neutral
Although ribavirin is effective but the rate of discontinuation due to anaemia is high especially in transplant recipients
All transplant recipients should be informed to avoid consuming processed undercoocked meat especially pork
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
Background
· Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide
· HEV infections are linked to the consumption of HEV contaminated meat products.
· Although HEV specific antibodies are thought to confer protection against re-infection, this still need to be proved.
· In immunosuppressed patients, however, acute HEV infection can progress to a chronic course with high morbidity and mortality rates. Case presentation
· A 64-year-old man with a history of FSGS underwent kidney transplantation.
· Immunosuppressive medication after transplantation included tacrolimus, mycophenolate mofetil and prednisone.
· Recurrence of FSGS occurred 2 months post transplantation for which he received rituximab and therapeutic plasma exchange.
· His post-transplantation course showed BKV viremia three months after transplantation, IS treatment was reduced for some time till viremia was controlled.
· 7 moths post transplantation, routine laboratory testing revealed elevated AST, ALT, and γ-GT. 4months later, he was clinically well but still, laboratory tests showed an increased γ-GT with 215IU/ L, but AST (44U/L) and ALT (45U/L) returned back to normal range. Abdominal ultrasound did not reveal hepatic lesions or signs of liver cirrhosis. Testing for hepatitis C virus RNA was negative, however, HEV RNA was detected using RT-PCR.
· Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7months beginning at 5 months post transplantation consistent with chronic HEV infection.
· Phylogenetic analysis of HEV RNA demonstrated an HEV genotype 3c.
· Stored plasma samples taken before kidney transplantation were positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before transplantation.
· Anti-HEV IgG showed a rapid rise after HEV RNA was first detectable.
· Anti-HEV IgM remained negative and it became positive, 4 months after detection of HEV RNA.
· To better appreciate the level of HEV IgG antibodies they used a quantitative HEV. Interestingly, it showed that the early samples tested (shortly after transplantation) HEV IgG were borderline and negative at 4 months. Subsequently, a rise in HEV IgG occurred at 10 month post -transplant.
· Later on treatment with ribavirin (200mg, 5 doses daily) was given for 11 weeks.
· HEV RNA in plasma was first negative one month after initiation of therapy and remained negative.
Discussion
· This case showed chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation.
· This suggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient.
· A definitive protective titer of anti-HEV IgG has not been firmly assessed yet.
· They used another quantitative assay which was calibrated against the WHO standard and it showed that anti-HEV IgG was below 7 IU/ ml supporting the hypothesis of non-protective antibody titers in our patient.
· Despite the rapid anti-HEV IgG response, this did not lead to clearance of HEV RNA from the blood in this case. This further supports the notion of a limited protective humoral immune response.
· Rituximab leading to impaired B cells in this immunosuppressed patient might have contributed to reinfection despite the presence of HEV antibodies.
· The T-cell mediated immune response remains largely unclear in HEV infection and deserves further study.
· They did not detect HEV RNA before and shortly after transplantation arguing against reactivation in our patient.
· Treatment with ribavirin was successful in this patient, in spite of discontinuation of antiviral therapy after 11 months treatment due to anemia. Conclusions
· Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
· In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing
Hepatitis E virus (HEV) infection is increasingly recognized worldwide as a major cause of acute hepatitis. Presentation of case was an immunocompromised patient who developed chronic HEV infection despitehe presence of high antibody levels. HEV infection was detected by RTPCR after diagnostic evaluation due to elevated liver enzymes. Retrospective analysis of stored serum samples revealed that this patient had been positive for HEV RNA for 7 months. Ribavirin successfully treated chronic HEV infection Essentials of Clinical Practice:
The presence of antiHEV IgG may not be protective, which limits the value of testing for anti-HEV IgG before starting immunosuppressive therapy. Clinical workup after elevated liver enzymes should include testing for HEV infection, regardless of anti-HEV IgG status prior to immunosuppression In immunocompromised patients, nucleic acid testing should be used to diagnose HEV infection.Four.Consumption of raw/undercooked pork products appears to be recommended for patients at risk of chronic HEV infection. In conclusion, we are able to identify a patient reinfected with HEV who develop a chronic course and was successfully treated with ribavirin. The role of humoral and T cell-mediated immune responses in cases of HEV re infection deserves further study.
Chronic HE infection after kidney transplantation with an antibody response suggestive of Reinfection Summary of the Article Background
HEV infection is increasingly recognized as a major cause of acute hepatitis worldwide.
Five genotypes are pathogenic to humans, with gt3 being the dominant HEV in Europe.
Transmission occurs via contaminated meat with HEV.
Usually, the infection is asymptomatic or presents as a mild and self-limited disease.
The immune response started with anti-IgM antibodies followed by HEV IgG response, IgG slowly declines but may persist over a years.
No definitive HEV antibody titre protective established till now.
In immunocompromised patients, acute HEV gt3 may progress to a chronic coarse, with a high morbidity and mortality.
Discussion
Although detectable anti-HEV IgG before and after kidney transplantation, HEV go into a chronic infection, this suggest HEV reinfection and indicate that HEV antibodies did not provide protection against HEV infection.
Protective antibody titre suggested to be 2.5 WHO units/ml , although a definitive protective titre have not yet established.
Choi and co-worker recently demonstrated that titre less than 6 will not be protective against HEV infection.
A French study found that a low anti-HEV IgG of < 7 WHO units/ml in immunocompromised patients did not protect against reinfection.
Impaired B cells (humoral response) were contribute to reinfection and itis vital to prevent reinfection as antibody alone fail to control the infection.
Rituximab and tacrolimus promote infection, while MMF inhibit HEV replication while steroid does not affect the virus.
Chronic HEV infection has been associated with impaired HEV-specific T-cell response in transplanted, but further study is needed.
Treatment with ribavirin was successful and it is a novel treatment till now with many side effects.
PEG-interferon carry a risk of rejection although offer antiviral activity.
Conclusion
Anti-HEV IgG may not be protective against reinfection, so, limited the value of estimating anti body titre before and after transplantation.
Clinical workup in elevetaed liver enzyme should include HEV infection irrespective of anti-HEV IgG status.
In immunocompromised patient HEV infection should be tested by using a nucleic acid testing.
Councelling the patient who at risk of HEV infection is to avoid consumption of raw/uncooked pig products.
Furthur study is needed to identify the role of humoral and cellular immune response in cases of HEV reinfection.
I like your well structured detailed summary in relation to each advice in relation to the type of disease and corresponding treatment. I appreciate your strategy in relation to Hep E infection and transplant.
Background
There are 5 HEV genotypes , genotype 3 is the most dominant in Europe .
Genotype 3 is transmitted zoonotically to humans through consumption of undercooked meat.
Usually it is asymptomatic and self limited.
Humoral immunity starts with Ig M rise then IgG which decreases but can persist for years meanwhile it’s protective role is controversial.
Genotype 3 can progress to a chronic course in immunocompromised cases.
This is a case report of a renal transplant recipient whom developed Chronic HEV infection shortly after transplantation . Case report
A 64-year-old male received kidney transplantation due FSGS in
April 2016.
Immunosuppressives for maintenance were ,tacrolimus, MMF and prednisone.
Also rituximab 750mg twice 3 months later and 26 times of plasma exchange for FSGS recurrence that was cured on October.
He had BK viremia 3 months after transplantation.
Prednisolone was tapered to 10 mg /day and MMF was reduced to 250 mg bid ,BK viremia level decreased less than 1000 copies /ml and MMF dose was doubled.
IVIG was given once in June 2016due to hypogammaglobulinemia.
5months later he had mild elevation of his liver enzymes and high gammaGT on routine testing with unremarkable hepatic imaging.
November 2017, his liver enzymes returned to normal but gamma GT was still elevated and unremarkable hepatic US findings ,he was on Tac 1 mg bid ,MMF 500 mg bid and prednisolone 7.5 mg OD.
HEV RNA was positive using RT-PCR, anti-HEV IgM and anti HEVIgG were positive by ELISA test.
Retrospective testing of stored plasma 7 months ago showed positive HEV denoting chronic HEV infection, positive for anti-HEV IgG and negative for anti-HEV IgM indicating cure before transplantation.
September 2016 ,Ig G level rose when HEV RNA was noticed and Ig M levels were negative then turned positive Feb 2017
It was analysed as HEV genotype 3.
September 2016 he started ribavirin for 11 weeks but was stopped due to anemia.
HEV RNA was negative in October 2017 and continued negative denoting cure . Liver enzymes were normalised .
Infection source was not discovered. Discussion
A case of chronic HEV infection with reinfection in a renal transplant recipient.
There is no specific protective titer for HEV Ab
A french study on immunocompromised patients demonstrated that a low anti-HEV IgG of < 7 WHO units/mL wont be protective against reinfection.
The current case experienced a rapid rise in anti-HEV IgG then an anti-HEV IgM response shortly afterwards but this immune response was not enough to clear the viral infection.
Rituximab could have affected HEV Ab production as in Immunocompromisation with impaired B cell might have lead to HEV reinfection.
In a study antibodies against the C-terminal end of ORF2 which have been regularly detected indicates the immune response of blood donors.
HEV IgG level decreased after immunosuppressive therapy indicating it’s influence on humoral response .
Immunosuppression affects HEV replication cycle.
Previous studies published that tac can enhance HEV infection, MMF inhibits it’s replication and steroids had no effect.
Chronic HEV infection impairs HEV specific T cell response.
In the current case with chronic HEV infection ,HEV-specific CD8+ Tcell response was diminished compared to acute disease , but was partially restored with ribavirin .
In fact ribavirin cleared the virus but anemia occurrence obliged them to stop it .
Peg INF can lead to rejection.
Regarding Sofosbuvir, further studies are needed. Conclusion –Analysis of HEV Ig G before immunosuppression is of limited importance as it is not protective.
-Elevation of liver enzymes necessitate testing for HEV infcetion regardless of HEV Ig G level before immunosuppression.
-HEV Nucleic acid testing is the method of diagnosis
in immunosuppressed cases
-Avoidance of undercooked meat need to be educated for cases at HEV infection risk.
– Further study is needed for humoral and T-cell mediated immune response in HEV reinfection.
I like your well structured detailed summary in relation to each advice in relation to the type of disease and corresponding treatment. I appreciate your strategy in relation to Hep E infection and transplant.
Case report; Summary Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
The recipient:
· A 64-year-old man, underwent KT after ESRD/FSGS onApril 2016.
· Immunosuppressive medication included tacrolimus, mycophenolate mofetil and prednisone.
· He received rituximab 750 mg twice and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma asreplacement fluid due to recurrence of FSGS, which subsequently resolved until October 2016.
· His post-transplantation course showed BKV viremia three months after transplantation and received IVIG once at the end of June 2016 due to hypogammaglobulinemia.
· November 2016, routine laboratory testing revealed elevated liver enzymes (AST,ALT & γ-GT) and liver ultrasound showed no pathological findings.
· March 2017, he was clinically well and his physical examination was without pathological findings. Still, laboratory tests showed an increased γ-GT but AST and ALT returned back to normal range. Abdominal ultrasound did not reveal hepatic lesions or signs of liver cirrhosis.
· Testing for hepatitis C virus RNA was negative. · HEV RNA was detected using RT-PCR indicating active HEV infection. Concomitantly anti-HEV IgM and IgG using ELISA were positive. · A fragment of open reading frame (ORF) demonstrated an HEV geno- type 3c. · Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection. · Stored plasma samples taken before kidney transplantation were positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before transplantation. · In September 2017, treatment with ribavirin (200 mg, 5 doses daily) was initiated. He received an 11- week course of ribavirin (off-label use) and therapy was stopped due to anemia. · October 2017, HEV RNA remained negative indicating successful therapy. Liver enzymes returned back to normal range. Discussion:
1. The mode of acquisition of HEV infection in this patient remains unclear but could be related to HEV- contaminated blood products, an HEV-contaminated transplant organ, or food uptake after transplantation.
2. Despite the presence of detectable anti-HEV IgG before and after kidney transplantation, HEV reinfection indicates that HEV antibodies did not confer protection in this patient.
3. Impaired B cells in this immunosuppressed patient might have contributed to reinfection despite the presence of HEV antibodies.
4. Reduction of anti-HEV IgG titers, shortly after transplantation, suggests an influence of the immuno- suppressive therapy on the humoral immune response.
5. Wang and colleagues showed that: tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect at all.
6. The T-cell mediated immune response remains largely unclear in HEV infection.
7. In this case repot, it was shown that the HEV-specific CD8+ T- cell response in chronic HEV patients was diminished in comparison to the acute disease course, but was partially restored after ribavirin therapy.
8. Although associated with anaemia, ribavirin is the only drug available for treatment of HEV infection.
9. Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
10.In vitro data showed that the drug sofosbuvir, known as a polymerase inhibitor of hepatitis C virus, may also be effective but beyond case reports no data is available to date. Conclusion:
1. This case underlines the importance of RT-PCR for HEV diagnostics in immunosuppressed patients and supports the notion that HEV antibodies do not confer universal protection.
2. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
3. Counseling patients at risk for chronic HEV infection seems advisable.
kidney transplantation with an antibody response suggestive of reinfection: a case report
Introduction: Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
The anti-HEV IgG antibody concentration slowly declines over time but may remain detectable for years.
HEV infection remains asymptomatic or presents as mild and self-limiting disease, HEV IgM detected early in disease and declines over time, HEV IgG may be detectable for years.
Five genotypes are known (genotype 3 is the dominant one in Europe), Seroprevalence rates range from <1%-52% across Europe.
In immunosuppressed patients, however, acute HEV Genotype 3 infection can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality rate.
HEV specific antibodies that confer protection against re-infection is controversial.
The Study Demonstrate theimportance of RT-PCR for diagnosing HEV in order to treat the patient early and prevent bad outcome post-transplant.
Aim of the study:
A case report of an immunocompromised patient who developed chronic HEV infection despite the presence of high-level antibodies (high anti-HEV IgG pre- and post-transplantation)
Case presentation: A 64-year-old male with ESRD 2/2 FSGS, Post kidney transplantation, and maintained on tacrolimus, mycophenolate, and prednisolone.
Patient received rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as replacement due to recurrence of focal segmental glomerulosclerosis, which subsequently resolved until October 2016.
History of BK viremia treated by reduction of immunosuppressive medications (MMF), and Intravenous immunoglobulins (10 g) were given once at the end of June 2016 due to hypogammaglobulinemia.
In November 2016, found to have modest elevation of liver function ALT 81, AST and gamma GT 276.
HEV RNA was detected using RT-PCR indicating active HEV infection. Concomitantly anti-HEV IgM and IgG using ELISA were positive. Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection.
Discussion: Immunosuppressive therapy affects the humoral immune response and interferes with the HEV replication cycle leading to low anti-HEV IgG titers. Chronic HEV infection is associated with an impaired HEV-specific T-cell response in transplant patients
The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti-HEV IgG before the start of immunosuppressive regimens. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
Tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect.
Ribavirin is the only drug available for treatment of HEV infection. Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection. Sofosbuvir (a polymerase inhibitor of hepatitis C virus), may also be effective. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti-HEV IgG before the start of immunosuppressive regimens. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression
In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing
Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
Conclusions: HEV reinfection with a chronic course is successfully treated with Ribavirin. Ribavirin is the drug of choice for treatment of HEV and anemia the common side effect of ribavirin.
HEV antibodies may not confer universal protection against HEV In immunosuppressed patients, RT-PCR for HEV diagnosis is important.
Serum samples before transplantation should be kept for testing HEV RNA when needed.
Counseling of patients at risk for chronic HEV infection is advisable,
The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
Background
Hepatitis E virus (HEV ) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
The anti-HEV IgG antibody concentration slowly declines over time but may remain detectable for years.
HEV specific antibodies are thought to confer protection against re-infection this topic remains controversial to date.
Acute HEV gt infection can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality rates.
In these patients the HEV specific antibody response is variable or lacking at large.
We report a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG preand post-transplantation and we describe and characterize the HEV-specific antibody response over time
Case presentation
A 64-year-old man with a history of focal segmental glomerulosclerosis underwent kidney transplantation in.
Immunosuppressive medication after transplantation included tacrolimus, mycophenolate mofetil and prednisone.
He received rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as.
The Creative Commons Public Domain Dedication waiver applies to the data made available in this article, unless otherwise stated
In March 2017, he had a routine follow-up visit at the transplant center and his medication included tacrolimus (1 mg twice daily, trough level 5–8 ng/mL), mycophenolate mofetil (500 mg twice daily), and prednisone (7.5 mg once daily)
He was clinically well and his physical examination was without pathological findings.
Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection .
Anti-HEV IgG showed a rapid rise after HEV RNA was first detectable in September 2016 whereas anti-HEV IgM remained negative.
Due to the retrospective nature of the HEV diagnosis no information on food consumption was possible Findings
Recent data demonstrated HEV seroprevalence rates ranging from < 1% up to 52% across Europe. Discussion and conclusions
We were able to show a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation
This suggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient.
In immunocompromised patients a French study found that a low anti-HEV IgG of < 7 WHO units/mL did not protect against reinfection.
We used another quantitative assay which was calibrated against the WHO standard.
The epitope-specific analysis of the immune response showed antibodies directed against the C-terminal end of ORF2 which have been regularly detected in another study analyzing the immune response of blood donors.
In our patient this was paralleled by an increase of anti-HEV IgG.
Anti-HEV IgG titers decreased shortly after transplantation suggestion an influence of the immunosuppressive therapy on the humoral immune response
The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study
Summarise this article Introduction
v HEV infection is a major cause of acute hepatitis worldwide
v Five genotypes are known (genotype 3 is the dominant one in Europe)
v Seroprevalence rates range from <1%-52% across Europe
v HEV specific antibodies that confer protection against re-infection is controversial
v Aim of the study: a case report of an immunocompromised patient who developed chronic HEV infection despite the presence of high level antibodies (high anti-HEV IgG pre- and post-transplantation)
Case presentation
A 64-year-old man underwent kidney transplantation in April 2016 (cause was FSGS). Immunosuppressive were tacrolimus, MMF and prednisone. Patient received rituximab 2 months after transplant and therapeutic plasma exchange with albumin and FFP as replacement fluid due to recurrence of FSGS. He developed BKV viremia and hypogammaglobulinemia three months after transplantation
Seven months after transplant, routine laboratory testing revealed elevated AST (62U/L), ALT (81U/L), and γ-GT (276U/L. Ultrasound of the liver was normal. Four months later, γ-GT is still high (215IU/ L) but AST and ALT returned back to normal range and HEV RNA was detected using RT-PCR. Anti-HEV IgM and IgG using ELISA were positive. Retrospective analysis of stored serum samples revealed that the patient was HEV RNA positive since 7months. In September 2017, treatment with ribavirin (200mg, 5 doses daily) was started (11week) with successful therapy
Discussion
o Immunosuppressive therapy affects the humoral immune response and interferes with the HEV replication cycle leading to low anti-HEV IgG titers
o Chronic HEV infection is associated with an impaired HEV-specific T-cell response in transplant patients
o Treatment with ribavirin was successful in our patient but anemia as well-known side effect of ribavirin led to the discontinuation of antiviral therapy
o Currently, ribavirin is the only drug available for treatment of HEV infection
o Pegylated interferon-alfa has antiviral activity against HEV, but has a high risk of rejection (not used)
o Sofosbuvir (a polymerase inhibitor of hepatitis C virus), may also be effective
For clinical practice:
1. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressive regimens
2. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression
3. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing
4. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable
Conclusions
o HEV antibodies may not confer universal protection against HEV
o In immunosuppressed patients, RT-PCR for HEV diagnosis is important
o Counseling of patients at risk for chronic HEV infection is advisable
o The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study
This article is about the importance of RT-PCR for diagnosing HEV in order to treat the patient early and prevent bad outcome post transplant. The study itself is based on a recipient who had a recurrence of Hepatitis E infection despite having high levels of antibodies.
Discussion
Chronic HEV infection is possible even if the patient has high levels of detectable anti HEV IgG antibodies before and after transplant. This means that HEV antibodies do not provide unconditional protection to the patient. According to WHO, a minimum antibody concentration of 2.5 units/mL can confer protection to the patient, although this is not without its limits. The patient can still develop chronic course of infection of hepatitis E.
Booster shots can lead to a rapid rise in anti HEV IgG followed by a rise in anti HEV IgM response. However, this may not lead to complete clearance of HEV RNA from the blood of the patient. This adds to the basic notion of limited protective humoral immune response that might allow space for reinfection, especially in immmunocompromised patients such as transplant recipients.
Since functional B cells are one of the mainline participants in controlling infection in the human body, impaired B cell function can contribute to risk of reinfection despite the presence of HEV antibodies in the immunocompromised patient.
Immunosuppressive agents also play a role in contributing to reinfection in the transplant recipient. Drugs such as tacrolimus have been documented to promote infection of liver cells with HEV whereas MMF inihibited HEV replication. Steroids remained neutral and did not appear to play a role at all in reinfection.
Thus, it is possible for the clinical course of HEV to be impacted by immunosuppressive regimen of the recipient, further underlining the importance of careful monitoring of immune response and serology of the patient upon administration of each of these immunosuppressive drugs, especially in the first year of transplantation.
Conclusion
Given all the data that we have seen with respect to HEV reinfection of transplant recipients, and the consensus that we have formed about the agents that can contribute to this risk, it is essential to note that HEV reactivation is not a common occurrence, but is actually rare.
Early detection through the usage of RT-PCR is paramount to managing the infection effectively, with ribavirin forming the frontline method of treatment. Anemia is a common side effect of this drug, and thus monitoring Hb levels, as well as making provisions for blood transfusions is essential for smooth application and completion of antiviral therapy.
PEG interferon has been described as an alternative treatment in cases which as resistant to ribavirin, but this cannot be used in patients with stem cell transplant or SOT with high risk of rejection.
Polymerase inhibitor of hepatitis C virus, Sofosbuvir, may be effective but this warrants further evidence before applying into proper clinical practice.
When increased liver enzymes are detected, it is important to do a clinical working for testing HEV infection irrespective of anti HEV IgG status before immunosuppression commenced. Nucleic acid testing is to be done.
Patient counseling regarding the bad effects of undercooking meat is an important measure to be taken for preventing or reducing the incidence of HEV infection in immunocompromised hosts.
Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
HEV infection remains asymptomatic or presents as mild and self-limiting disease, HEV IgM detected early in disease and declines over time, HEV IgG may be detectable for years.
In immunosuppressed patients, however, acute HEV G3 infection can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality rate.
Case presentation: A 64-year-old male with ESRD secondary to FSGS, underwent a kidney transplantation, and maintained on tacrolimus, mycophenolate, and prednisolone. The Pt. received rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as replacement fluid due to recurrence of focal segmental glomerulosclerosis, which subsequently resolved until October 2016. H/O BK viremia treated by reduction of immunosuppressive medications (MMF), and Intravenous immunoglobulins (10 g) were given once at the end of June 2016 due to hypogammaglobulinemia. In November 2016, found to have modest elevation of liver function ALT 81, AST and gamma GT 276. HEV RNA was detected using RT-PCR indicating active HEV infection. Concomitantly anti-HEV IgM and IgG using ELISA were positive. Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection. Discussion: 1. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti-HEV IgG before the start of immunosuppressive regimens. 2. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression. 3. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing. 4. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable. 5. tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect. 6. Ribavirin is the only drug available for treatment of HEV infection. Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection. Conclusion: HEV reinfection with a chronic course is successfully treated with Ribavirin. Serum samples before transplantation should be kept for testing HEV RNA when needed. The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
AIM OF Article
I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing
. IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
V. identify a patient with HEV reinfection who developed a chronic course which was successfully treated with ribavirin.
Case presentation
A 64Y man with a history of FSGS underwent kidney transplantation2016
On tacrolimus, mycophenolate mofetil and prednisone. Had recurrence of FSGS received rituximab -therapeutic plasma exchange
Had BKV INFECTION 3 MONTH AFTER TRANSPLANT AND TREATED
Had evealed elevated AST – ALT , and γ-GT
Abdominal ultrasound did not reveal hepatic lesions or signs of liver cirrhosis.
Testing for hepatitis C virus RNA was negative,
HEV RNA was detected using RT-PCR indicating active HEV infection. Concomitantly anti-HEV IgM (71.5 AU/mL) and IgG (149 AU/mL) using ELISA were positive.
To better appreciate the level of HEV IgG antibodies we used a quantitiative HEV ELISA (Anti-HEV ELISA, Euroimmun), which was calibrated against the WHO standard and expresses HEV IgG in IU/ml. Interestingly, we were able to show that the early samples tested HEV IgG borderline (April 2016) and negative (August 2016), respectively
He received an 11- week course of ribavirin and therapy was stopped due to anemia. HEV RNA in plasma was first negative in October 2017 and remained negative indicating successful therapy.
Liver enzymes returned back to normal range.
The mode of acquisition of HEV infection in this patient remains unclear but could be related to HEV contaminated blood products, an HEV-contaminated transplant organ, or food uptake after transplantation
Upon review of the clinical charts we could exclude the administration of blood transfusions shortly before transplantation. The patient had no recent travel. Due to the retrospective nature of the HEV diagnosis no information on food consumption was possible.
Discussion and conclusions
a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation. This suggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient.
HEV antibodies are considered to be pivotal to control the infection.
Recently, HEV antibodies have been standardized and a minimum protective antibody concentration of 2.5 World Health Organization (WHO) units/mL has been proposed . However, a definitive protective titer has not been firmly assessed yet.
Choi and coworkers recently demonstrated that rhesus macaques with low HEV-IgG titers (< 6 IU/ml) were not protected against HEV reinfection
in immunocompromised patients a French study
found that a low anti-HEV IgG of < 7 WHO units/mL did not protect against reinfection
Interestingly two issue in our case 1-our patient showed a rapid rise in anti-HEV IgG which was followed by an anti-HEV IgM response shortly after. This pattern is typical for a booster immune response and has been demonstrated for HEV in vivo . However, despite the rapid anti-HEV IgG response this did not lead to clearance of HEV RNA from the blood in our patient. This further supports the notion of a limited protective humoral immune response.
2-the rituximab induced B cell depletion might have influenced the development of HEV antibodies in our patient but anti-HEV IgG levels did never fall below the cut-off of the assay. It has been shown that functional B cells are instrumental to control the infection and that antibodies might not be the only correlate of protection Thus, impaired B cells in our immunosuppressed patient might have contributed to reinfection despite the presence of HEV antibodies.
T-cell mediated immune response
chronic HEV infection has been associated with an impaired HEV-specific T-cell response in transplant patients
However, the T-cell mediated immune response remains largely unclear in HEV infection
HEV-specific CD8+ Tcell response in chronic HEV patients was diminished in comparison to the acute disease course, but was partially restored after ribavirin therapy our patient developed chronic HEV infection which can lead to rapidly developing cirrhosis and liver failure
Treatment with ribavirin was successful in our patient but anemia as well-known side effect of ribavirin led to the discontinuation of antiviral therapy.
Currently, ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently needed.
Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
One of theincreasing causes of acute hepatitis globally now is hepatitis E with a prevalence that varies from <1% to up to 52% in Europe. There are about 5 recognized genotypes with genotype 3 being very common in Europe and transmitted zoonotically to humans. Among the immunosuppressed, acute HEV can progress to a chronic with high morbidity and mortality
Case presentation
A 64-year-old man had KTP in April 2016 following FSGS as the primary etiology and was on tacrolimus-based immunosuppression
He had 26 sessions of plasmapheresis 2 months post-KTP following a recurrence of the primary disease
He developed the BK virus 6 months post-KTP and recovered following IR and IVIG
In November 2016, there was a rise in liver enzymes and the aminotransferase later dropped but not the GGT
Test for HEV RNA came back positive with anti-HEV IgM and IgG also positive
The retrospective stored sample was positive for HEV RNA, and IgG but negative for IgM
In September 2017, treatment with ribavirin was administered following a consistent rise in liver enzymes and there was a recovery
Discussion and Conclusion
A case of HEV infection with the presence of anti-HEV IgG before and after the transplant
The impaired B cell through the use of rituximab might have contributed to reinfection despite the presence of anti-HEV
The anti-HEV IgG titers decreased shortly after transplantation suggesting an influence of the immunosuppressive therapy
The study has shown that They showed that tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect at all
Clinically, the index case developed chronic HEV infection which can progress to cirrhosis if not treated early
Adequate proper counseling should be done for KTP patients to avoid the consumption of undercooked pork meat
The presence of anti-HEV IgG in a patient may not be protective against the virus reactivation of infection.
The role of the humoral and T-cell-mediated immune response in cases of HEV reinfection deserves further study.
HEV infection is a major cause of acute hepatitis worldwide.
5 human genotypes known, genotype3 is the dominant in Europe.
Sero-prevalence of HEV range from<1%-52% across Europe.
Genotype3 transmitted through contaminated meat.
Role of anti-HEV abs in protection against reinfection is controversial.
Acute HEV infection can progressed to chronic infection in immunosuppressed patients with high mortality & morbidity.
CASE:
At April,2016 renal transplantation done for patient with ESRD due to FSGS.
Maintenance immunosuppression were CNI, MMF & steroids.
Rituximab & PE used for disease recurrence treatment (resolution achieved after 4 months of treatment).
3 moths post transplant, the recipient develop BKV viremia treated by reduction of steroid dose to 10mg/day & MMF 250mg twice daily(MMF increased to 500mg twice daily after reduction of BKV viral load).
During follow-up lab test, liver enzymes found to be persistently elevated with normal liver US.
HCV RNA was negative, but HEV RNA was positive (active infection).
Retrospective examination of stored plasma samples show presence of antiHEV ab(IgG) before transplantation& negative IgM abs. Also HEV RNA detected 5 months post transplant
Treatment with ribavirin started & continued for only 11 months due to development of anemia.
HEV RNA after treatment was undetected & liver enzymes returned to normal.
Discussion:
Chronic HEV infection can be occur despite presence of antiHEV IgG pre- & post transplantation.
Minimum Ab protective concentration is 2.5WHO IU/ml, but in French study found that Ab concentration <7WHOIU/ml was not protective against reinfection.
It was found that there was rapid rise of IgG after infection, but it can’t clear the virus from patient blood.
Impaired B cell due to use of rituximab may be responsible of reinfection despite presence of HEV Abs.
Tacrolimus can promote infection of liver cells with HEV while MMF inhibit viral replication & steroid has no effect.
HEV specific T-cell impairment in transplantation have a role in chronic HEV infection.
Ribavirin is the only available treatment, PEG-INF can be effective but associated with high risk of rejection.
Vitro data shows effectiveness of sofosbuvir, but available data only from case report.
Important points:
Anti-HEV IgG not protective & value of testing of it pre transplant is limited.
Any immunocompromised patient with increased liver enzymes, the workup should include testing of HEV infection regardless IgG status before immunosuppression.
Diagnosis of HEV in immunocompromised done by RNA detection.
Advise SOT recipients about the risk of HEV infection if consume raw or undercook pig meats.
Role of humoral & T cells immunity in HEV reinfection need further studies.
IV. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
==================================================================== Summarise this article
Background
Hepatitis E virus (HEV) infection is a major cause of acute hepatitis worldwide, with five human pathogenic HEV genotypes known.
HEV genotype 3 (gt3) is the dominant genotype in Europe, with seroprevalence rates ranging from < 1% up to 52%.
HEV infection is transmitted zoonotically to humans and is linked to the consumption of HEV contaminated meat products.
In immunosuppressed patients, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates.
We report a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG pre- and post-transplantation.
==================================================================== Case presentation
A 64-year-old man with a history of focal segmental glomerulosclerosis underwent kidney transplantation in April 2016 and received immunosuppressive medication, including tacrolimus, mycophenolate mofetil, prednisone, rituximab, and therapeutic plasma exchange.
His posttransplantation course showed BKV viremia three months after transplantation, and he was tapered to 10 mg/d and reduced to 250 mg twice daily.
In November 2016, routine laboratory testing revealed elevated AST, ALT, and γ-GT. Ultrasound of the liver showed no pathological findings.
The patient had a routine follow-up visit in March 2017 and his medication included tacrolimus, mycophenolate mofetil, and prednisone.
Laboratory tests showed an increased γ-GT with 215 IU/L, but AST and ALT returned to normal range.
HEV RNA was detected using RT-PCR, and anti-HEV IgM and IgG were positive.
Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months, consistent with chronic HEV infection.
Anti-HEV IgG antibodies (recomLine HEV IgG, Mikrogen) were detected against the C-terminal end of the ORF2 protein and the full-length ORF3 protein of HEV gt1 and 3 (O3Gt1 and O3Gt3).
A quantitiative HEV ELISA (Anti-HEV ELISA, Euroimmun) was also used to measure the level of antibodies.
The early samples tested borderline and negative, respectively, before kidney transplantation.
The mode of acquisition of HEV infection in this patient remains unclear, but it could be related to contaminated blood products, an HEV-contaminated transplant organ, or food uptake after transplantation.
==================================================================== Discussion and conclusions
This study showed a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation.
Cases of HEV reinfection leading to chronic courses have been described anecdotally, but comprehensive data is lacking.
HEV antibodies are considered to be pivotal to control the infection, and a minimum protective antibody concentration of 2.5 World Health Organization (WHO) units/mL has been proposed.
However, a definitive protective titer has not been firmly assessed yet.
Additionally, HEV serological assays differ in their performance and standardization of antibody assays is under debate.
Finally, our patient showed a rapid rise in anti-heV IgG which was followed by an anti-hev IgM response shortly after, but this did not lead to clearance of HEV RNA from the blood in our patient, suggesting a limited protective humoral immune response.
Immunosuppressive therapies may have influenced the development of HEV antibodies in immunosup-pressed patient, as epitope-specific analysis showed antibodies directed against ORF2.
Anti-HEV IgG titers decreased shortly after transplantation, suggesting an influence of immuno-suppressive therapy on the humoral immune response.
Chronic HEV infection is associated with impaired HEV-specific T-cell response, which can lead to cirrhosis and liver failure.
Ribavirin is the only drug available for HEV infection, but novel treatments are needed. Pegylated interferon alfa has antiviral activity, but cannot be used in patients with stem cell or organ transplants.
Testing for anti-HEV IgG before immunosuppression is important, diagnosing HEV infection using nucleic acid testing, counseling patients at risk, and treating HEV reinfection with ribavirin.
RT-PCR is essential for HEV diagnostics in immunosuppressed patients, but HEV antibodies do not confer universal protection.
Acute hepatitis is increasingly linked to HEV infection. Five human pathogenic HEV genotypes are known, with HEV genotype 3 (gt3) dominating in Europe. HEV seroprevalence in Europe ranged from 1% to 52%. HEV gt3 is spread zoonotically to humans by eating HEV-contaminated meat. HEV infection usually causes minor, self-limiting symptoms.
Case presentation:
We report on an immunocompromised patient who, despite having high levels of antibodies, had a persistent HEV infection. During the diagnostic assessment, elevated liver enzymes led to the suspicion of HEV infection, which was confirmed by RT-PCR. We found out that the patient had been HEV RNA positive for the last seven months after doing a retrospective examination of stored blood samples. Ribavirin was able to effectively cure a chronic HEV infection in a patient.
Discussion:
Anecdotal evidence of HEV reinfection causing chronic disease is scarce. Controlling infection requires HEV antibodies. HEV antibodies have been standardized, and a minimum protective antibody concentration of 2.5 WHO units/mL is suggested. Nevertheless, a protective titer has not been determined. Choi and colleagues found that low HEV-IgG titers (< 6 IU/ml) did not protect rhesus macaques against HEV reinfection.
Conclusion:
the patient had a chronic course of HEV infection, which was effectively treated with ribavirin. This information may be found in the conclusion section. This instance demonstrates the significance of RT-PCR for HEV diagnosis in individuals with immunosuppression and lends credence to the idea that HEV antibodies may not provide universal protection against infection. It is prudent to provide counseling to individuals who are at risk for chronic HEV infection. It is important to do more research on the function that humoral and T-cell-mediated immune responses play in instances of HEV reinfection.
Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
There are five human pathogenic HEV genotypes .
HEV genotype 3 (gt3) is the dominant HEV genotype in Europe.
HEV gt3 is transmitted zoonotically to humans and infections are linked to the consumption of HEV contaminated meat products.
In general, HEV infection remains asymptomatic or presents as mild and self-limiting disease. In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates.
Chronic HEV infection have been reported to develop in patients with detectable anti-HEV IgG before and after kidney transplantation. This suggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient.
This reported case demonstrated an immunocompromised patient who developed chronic HEV infection despite the presence of high level antibodies.
THIS ARTICLE DEMONSTRAED THE FOLLOWING IMPORTANT CLINICAL POINTS :
I.The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti- HEV IgG before the start of immunosuppressive
regimens.
II.Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III.In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV.Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
V. Patient with HEV reinfection who developed a chronic course can be successfully treated with ribavirin .
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
A 64-year-old man with a history of focal segmental glomerulosclerosis underwent kidney transplantation in April 2016.
Standard tacrolimus, mycophenolate mofetil and prednisone immunosuppression.
In addition, he received rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma to prevent recurrence of FSGS.
BKV viremia three months after transplantation.
Initially MMF and steroid was reduced, but after control of BKV, MMF dose was increased.
November 2016, routine laboratory testing revealed elevated AST, elevated ALT and elevated γ-GT
Ultrasound of the liver showed no pathological findings.
In march 2017, AST and ALT levels normalized, but there was elevated γ-GT
HCV negative, but HEV RNA was detected using RT-PCR.
Anti-HEV IgM and IgG using ELISA were positive.
Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection.
The stored plasma samples taken before kidney transplantation were positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before transplantation.
In September 2017, treatment with ribavirin (200 mg, 5 doses daily) was initiated.
He received an 11- week course of ribavirin (off-label use) and therapy was stopped due to anaemia. HEV RNA in plasma was first negative in October 2017 and remained negative indicating successful therapy. Liver enzymes returned back to normal range.
The mode of acquisition of HEV infection in this patient remains unclear.
This case highlights HEV reinfection and indicates that HEV antibodies did not confer protection in this patient.
HEV antibodies have been standardized and a minimum protective antibody concentration of 2.5 World Health Organization (WHO) units/mL has been proposed.
Conclusion:
The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti-HEV IgG before the start of immunosuppressive regimens.
Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable
This patient has HEV reinfection who developed a chronic course which was successfully treated with ribavirin.
The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
1- HEV incidence is increasing worldwide and constitute major cause of acute hepatitis.
2- Its route of administration by ingestion of infected meat zoonotic transmission.
3- Can be asymptomatic, or mild or severe fulminant hepatitis and can be self-limited.
4- It is 5 genotypes, genotype 3 is the most common especially in Europe.
5- Immune response started by elevation of IgM antibody in acute stage followed by appearance of IgG which decrease slowly over the time and may persist for years.
6- In immunosuppressed patient, the immune response cannot be guaranteed; also, chronic hepatitis can be developed with high morbidity and mortality.
7- HEV IgG does not offer protection against re-infection and can be increased after transplantation even if it was present pre-transplantation.
8- No definite protective titer of IgG antibodies.
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: Introduction;
-Hepatitis E virus (HEV) infection is now recognized as a major cause of acute hepatitis worldwide.
-To date, five human pathogenic HEV genotypes are known, of which HEV genotype 3 (gt3) is the dominant HEV genotype in Europe.
-HEV gt3 is transmitted zoonotically to humans and infections are linked to the consumption of HEV contaminated meat products.
-In general, HEV infection remains asymptomatic or presents as mild and self-limiting disease.
-In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality rates. Aim;
-Here, they report a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG pre- and post-transplantation.
-They describe and characterize the HEV-specific antibody response over time. Methodology;
-They report a case who is (64-year-old man with a history FSGS underwent kidney transplantation in April 2016, who received rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as replacement fluid due to recurrence of FSGS, which subsequently resolved until October 2016).
-This immunocompromised patient was clinically well pre-transplantation and his physical examination was without pathological findings.
-He developed chronic HEV infection despite the presence of high level antibodies.
-HEV infection was detected using RT-PCR upon diagnostic evaluation due to increased liver enzymes. Upon retrospective analysis of stored serum samples. Results;
-They found that the patient since 7 months was positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before transplantation.
-Chronic HEV infection was successfully treated with ribavirin (200 mg , 5 doses daily).
-He received an 11- week course of ribavirin and therapy was stopped due to anemia.
-The mode of acquisition of HEV infection in this patient remains unclear; but could be related to HEV contaminated blood products, an HEV-contaminated transplant organ, or food uptake after transplantation. Discussion;
-In current casesuggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient.
-Interestingly, the rituximab induced B cell depletion might have influenced the development of HEV antibodies in this patient.
-Thus, impaired B cells in our immunosuppressed patient might have contributed to reinfection despite the presence of HEV antibodies.
-Immunosuppressive therapies might also interfere with the HEV replication cycle; that tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect at all .
-They were able to show that the HEV-specific CD8+ Tcell response in chronic HEV patients was diminished in comparison to the acute disease course, but was partially restored after ribavirin therapy.
-Treatment with ribavirin was successful in our patient but anemia as well-known side effect of ribavirin led to the discontinuation of antiviral therapy.
-Currently, ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently needed.
-Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection. Conclusions;
-The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti-HEV IgG before the start of immunosuppressive regimens.
-Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
-In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
-Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
-The patient suffered from a chronic course of HEV infection, which was successfully treated with ribavirin.
-The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
-This a case report study with (LOE IV)
Hepatitis E virus (HEV) infection is one of the important causes of acute viral hepatitis across the globe.
Five genotypes; genotype3(gt3) is most common in Europe and it is transmitted mainly through consumption of HEV contaminated meat (zoonosis).
HEV specific antibodies may or may not confer long lasting immunity against the virus.
HEV infection in immnue compromised host may progress to chronic hepatitis and associated with poor outcome.
This is a case report of chronic HEV in a kidney transplant recipient diagnosed in the first 3 months after transplantation though the patient had high HEV specific antibodies
Case report
A 64 years old male transplanted in April due to focal segmental glomerulosclerosis (FSGS). Unfortunately had had a bad year due complications (recurrent FSGS, BKV viremia, hypogammaglobulinemia). In November 2016 developed mild transaminitis (ALT 81, AST 62, GGT 276 U/L) with normal liver ultrasounography. In March 2017 only GGT remained elevated at 215 U/L. Further tests confirmed; HEV RNA PCR , anti-HEV IgM & IgG were positive. His stored plasma sample over the previous 7 months was positive for HEV RNA but samples taken before transplantaion was positive for anti-HEV IgG and negative for both HEV RNA PCR and anti-HEV IgM i.e., resolved HEV infection. Genotying showed gt3 and he was treated for around 3 months by ribavirin 200g 5 times /day in September 2017. Ribavirin was discontinued due to anemia but his viral load was undetectable and treated successfully. It was not clear how he acquired HEV and possibilities may be contaminated food or the transplanted organ.
Take home messages
Anti-HEV specific antibodies may not lead to long lasting protection.
HEV re-infection may progress to chronic infection in immune compromised host.
Counseling at risk of chronic hepatitis to avoid eating raw or under cooked animal products
In immune compromised patient with liver dysfunction, testing for HEV RNA PCR is essential
Ribavirin is the drug of choice for treatment of HEV and anemia the common side effect of ribavirin.
HEV – 5 genotypes gt3 most dominant in Europe. HEV seroprevalence 1% to 52% transmitted via consumption of contaminated meat products. HEV infection – asymptomatic mild or self limiting disease
infection fl b rise in anti HEV Ig M flb rise in Ig G, which then slowly declines.
In immunosuppressed patients acute HEV gt3 can progress to Chronic HEV, which is HEV RNA detectable > 6 months.
Case 64 yr old man F S G S ~ native kidney disease Post Tx in April 2016 on Tac, MMF, prednisone. In June 2016, F SGS recurrence – 2 dose of Rituximab and 26 session of plasmapharesci done.
Had BK viraemia Prednisone tapered to 10 mg lday MMF reduced to a dose of 250 mg BD settled
In November 2016 AST 62 U/L USG – normal
March 2017 AST-44, ALT -45 but gamma GT 215 USG abdomen – normal Hep C RNA – HEV RNA detected HEY Ig M and Ig G positive HEV RNA positive in retrospective samples from 7 months. So chronic HEV. genotype was 3c. pre transplant sample showed HEV Ig G +
Treatment Ribavirin 200mg 5 times daily for 11 weeks HEV RNA became negative and remained so. Liver enzymes became normal.
Discussion Case of HEV reinfection inspite of HEV Ig G + pre transplant. low anti – HEV <7 WHO units/ ml did not protect against reinfection. Also surprising was initially Ig G showed rapid rise f/b Igm. Also impaired B cells clue to Rituximab contributed. IgG Titre decreased post Tx due to immunosuppression. Tacrolimus promotes HEV infection of liver cells, MM F prevents. HEV specific CD8+ Tcell response in chronic HEV patients was diminished, which was partially restored by Ribavirin therapy. Treatment with Ribavirin was successful but needed to be stopped due to anaemia.
Summary anti Ig G HEV may not be protective. test For HEV when liver enzyme deranged Diagnose HEV using NAT Advise against consuming raw/ undercooked pig products.
Chronic hepatitis E after kidneytransplantation with an antibody responsesuggestive of reinfection: a case report
BackgroundHepatitis E virus (HEV) infection is increasingly recognizedas a major cause of acute hepatitis worldwide.
To date, five human pathogenic HEV genotypes are known. The dominant one in Europe is genotype 3 (gt3) which is transmitted zoonotically to humans
HEV infection remains asymptomatic or presents as mild and self-limiting disease.
The humoral immune response begins with the rise of anti-HEV IgMantibodies followed by the development of a robust antiHEV IgG response.
The anti-HEV IgG antibody concentration then slowly declines over time but may remain detectable for years.
In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates. In these patients the HEV specific antibody response is variable or lacking at large.
In the following case report:
The authors reported a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG pre- and post-transplantation and they described and characterized the HEV-specific antibody response over time.
Case presentation:
The authors report an immunocompromised patient who developed chronic HEV infection despite the presence of high level antibodies. HEV infection was detected using RT-PCR upon diagnostic evaluation due toincreased liver enzymes. Upon retrospective analysis of stored serum samples we found that the patient was HEVRNA positive since 7 months. Chronic HEV infection was successfully treated with ribavirin.
For clinical practice the following points remain important:I. The presence of anti-HEV IgG may not beprotective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressiveregimens.II. Clinical work-up upon increased liver enzymesshould include testing for HEV infectionirrespective of the anti-HEV IgG status beforeimmunosuppression.III. In immunosuppressed patients HEV infectionshould be diagnosed using nucleic acid testing.IV. Counseling patients at risk for chronic HEVinfection regarding the consumption of raw/undercooked pig products seems advisable.V. In conclusion, we were able to identify a patientwith HEV reinfection who developed a chroniccourse which was successfully treated withribavirin. The role of the humoral and T-cellmediated immune response in cases of HEVreinfection deserves further study.
Conclusions: In conclusion, the patient suffered from a chronic course of HEV infection, which was successfullytreated with ribavirin. Our case underlines the importance of RT-PCR for HEV diagnostics in immunosuppressedpatients and supports the notion that HEV antibodies do not confer universal protection. Counseling patients at riskfor chronic HEV infection seems advisable. The role of the humoral and T-cell mediated immune response in casesof HEV reinfection deserves further
Chronic hepatitis E after kidneytransplantation with an antibody responsesuggestive of reinfection: a case report
BackgroundHepatitis E virus (HEV) infection is increasingly recognizedas a major cause of acute hepatitis worldwide.
To date, five human pathogenic HEV genotypes are known. The dominant one in Europe is genotype 3 (gt3) which is transmitted zoonotically to humans
HEV infection remains asymptomatic or presents as mild and self-limiting disease.
The humoral immune response begins with the rise of anti-HEV IgMantibodies followed by the development of a robust antiHEV IgG response.
The anti-HEV IgG antibody concentration then slowly declines over time but may remain detectable for years.
In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates. In these patients the HEV specific antibody response is variable or lacking at large.
In the following case report:
The authors reported a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG pre- and post-transplantation and they described and characterized the HEV-specific antibody response over time.
Case presentation:
The authors report an immunocompromised patient who developed chronic HEV infection despite the presence of high level antibodies. HEV infection was detected using RT-PCR upon diagnostic evaluation due toincreased liver enzymes. Upon retrospective analysis of stored serum samples we found that the patient was HEVRNA positive since 7 months. Chronic HEV infection was successfully treated with ribavirin.
For clinical practice the following points remain important:I. The presence of anti-HEV IgG may not beprotective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressiveregimens.II. Clinical work-up upon increased liver enzymesshould include testing for HEV infectionirrespective of the anti-HEV IgG status beforeimmunosuppression.III. In immunosuppressed patients HEV infectionshould be diagnosed using nucleic acid testing.IV. Counseling patients at risk for chronic HEVinfection regarding the consumption of raw/undercooked pig products seems advisable.V. In conclusion, we were able to identify a patientwith HEV reinfection who developed a chroniccourse which was successfully treated withribavirin. The role of the humoral and T-cellmediated immune response in cases of HEVreinfection deserves further study.
Conclusions: In conclusion, the patient suffered from a chronic course of HEV infection, which was successfullytreated with ribavirin. Our case underlines the importance of RT-PCR for HEV diagnostics in immunosuppressedpatients and supports the notion that HEV antibodies do not confer universal protection. Counseling patients at riskfor chronic HEV infection seems advisable. The role of the humoral and T-cell mediated immune response in casesof HEV reinfection deserves further study.
A 64-year-old man who has kidney transplantation in April 2016 who had elevated AST (62 U/L, normal range < 50 U/L), ALT (81 U/L, normal range < 50 U/L), and γ-GT (276 U/ L, normal range < 60 U/L) on routine testing on nov 2016. In March 2017, he had γ-GT with 215 IU/ L, but AST (44 U/L) and ALT (45 U/L) returned back to normal range. HEV RNA was detected using RT-PCR . Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection. Interestingly, stored plasma samples taken before kidney transplantation were positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before transplantation. In September 2017, treatment with ribavirin (200 mg, 5 doses daily) was initiated. His liver values were AST (77 U/ L), ALT (78 U/L), and γ-GT (226 U/L). He received an 11- week course of ribavirin (off-label use) and therapy was stopped due to anemia.
This case illustrates that the work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
HEV infection –one of the causes of acute hepatitis globally but it can progress to chronic hepatitis in some cases with high morbidity and mortality. To date, five genotypes have been known. Less than 1-52% patients have been found positive for HEV in Europe. Anti-HEV antibody persists throughout life but had controversial opinion about conferring protection against re-infection.
Aim of the study:
A case report of renal transplant patient who developed chronic HEV infection shortly after transplant despite the presence of high level antibodies.
Case presentation
A 64 year female was started on triple immunosuppression including tacrolimus, mycophenolate, and prednisolone after renal transplant. Primary cause of ESRD was FSGS.FSGS recurred after transplant and treated with therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as replacement fluid. Later also given rituximab 750 mg twice to achieve remission which was achieved in in June 2016.Three months later developed BK viremia for which immunosuppression(MMF) was reduced and IVIG administered ,copies of BK virus becomes undetectable. In November 2016, patient had elevation of liver function ALT ,AST and gamma GT .HEV RNA was being advised and comes out to be positive along with anti-HEV IgM and IgG using ELISA indicating active HEV infection. Patient was being treated with Ribavirin for 11 months after which it was stopped due to anemia. Liver function tests and PCR for HEV RNA becomes negative after treatment.
CONCLUSION:
No long lasting protection due to anti-HEV antibodies.
Counseling to avoid raw or under cooked animal products.
HEV RNA PCR is essential and should be done in cases of liver dysfunction.
Ribavirin is the only treatment option available.
Summarise this article:
Patient had an ESRD due to FSGS, had an acute rejection due to recurrence of FSGS, for which he received PF and rituximab, He also had BKV infection which respond to IS reduction.
Patient developed an elevation of liver enzyme he found to have HEV infection by HED RNA.
Stored plasma shows HEV IgG, but no evidence of IGM, which imply previous infection.
Patient received Ribavirin to treat HEV infection, though he developed anemia, which necessities scission of medication, he respond to treatment.
Conclusion:
IgG against HEV not confer protection against HEV reinfection.
HEV RNA and/or antigen detection must be used to diagnose HEV.
Individuals must receive written advice regarding the risk of HEV from undercooked meat (particularly processed pork) before and after transplantation, treatment available is Ribavirin, which should be follow for anemia complication.
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report.
Background
Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide. There is a five human pathogenic HEV genotypes are known, of which HEV genotype 3 (gt3) is the dominant HEV genotype in Europe.
HEVgt3 is transmitted zoonotically to humans and infections are linked to the consumption of HEV contaminated meat products. In general, HEV infection remains asymptomatic or presents as mild and self-limiting disease.
In immunosuppressed patients, , acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates. in these patients the HEV specific anti body response is variable or lacking at large.
Case presentation
A 64-year-old man with a history of focal segmental glomerulosclerosis underwent kidney transplantation in April 2016. Immunosuppressive medication after trans plantation
included tacrolimus, mycophenolate mofetil and prednisone. In addition, he received rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as replacement fluid due to recurrence of focal segmental glomerulosclerosis, which subsequently resolved until October 2016. His post-transplantation course showed BKV viremia three months after transplantation. Which is controlled with reduction of immunosuppression. Intravenous immune globulins (10 g) were given once at the end of June 2016 due to hypogammaglobulinemia.
in November 2016, routine laboratory testing revealed elevated AST, ALT, and gamma –GT. HEV RNA was detected using RT-PCR. Concomitantly anti-HEV IgM and IgG were positive.
Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection.
stored plasma samples taken before kidney transplantation were positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before trans plantation.
In September 2017, treatment with ribavirin (200 mg, 5doses daily) was initiated.
discussion and conclusions:
this article show a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation. This suggests HEV re-infection and indicates that HEV antibodies did not confer protection in this patient.
HEV antibodies have been standardized and a minimum protective antibody concentration of 2.5 (WHO)
units/mL has been proposed. However, a definitive protective titer has not been firmly assessed yet.
Beyond the humoral response and the immunosuppressive therapy chronic HEV infection has been associated with an impaired HEV-specific T-cell response in transplant patients.
Cases of reactivation of HEV have been rarely described to date . We did not detect HEV RNA before and shortly after transplantation arguing against reactivation in this patient.
This patient developed chronic HEV infection which can lead to rapidly developing cirrhosis and liver failure.
Treatment with ribavirin was successful in this patient but anemia as well-known side effect of ribavirin led to the discontinuation of antiviral therapy. Currently, ribavirin is the only drug available for treatment of HEV infection.
Important clinical practice point:
I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti- HEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
V. In conclusion, this article identify a patient with HEV reinfection who developed a chronic course which was successfully treated with ribavirin.
Summarise this article;
This article discus the chronic HEV infection of a case with post-transplantation, this is a case of a 64-years –old man with history of FSGS was transplanted and received immunosuppression.
Now recurrence of disease started treated as rejection, then BK viremia, improved.
Now presented with elevated transaminases with clinical symptoms,
Further workup done showed HEV RNA PCR positive.
In September 2017, the recipient was given ribavirin for 11 weeks, although treatment was stopped to Anemia.
However, in October the enzymes become normal and HEV PCR become negative.
Discussion, conclusion;
According to WHO the minimal protective threshold for anti-HEV titers should be >6 units/ml to give protection.
Only treatment is ribavirin,
However, the case report demonstrate that anti-HEV IgG may not be protective in immunosuppressed patient.
It’s crucial to advice the recipient about diet.
A 64-year-old man with a history of focal segmental glomerulosclerosis underwent kidney transplantation and received immunosuppressive medication. After transplantation, he had BKV viremia which was managed by adjusting the dosage of the immunosuppressive medication. In November 2016, routine laboratory testing revealed elevated liver enzymes and HEV RNA was detected using RT-PCR indicating active HEV infection. Concomitantly, anti-HEV IgM and IgG were positive. Retrospective analysis showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection. Treatment with ribavirin was initiated, and therapy was stopped due to anemia. HEV RNA in plasma was first negative in October 2017 and remained negative indicating successful therapy. The mode of acquisition of HEV infection in this patient remains unclear but could be related to HEV-contaminated blood products, an HEV-contaminated transplant organ, or food uptake after transplantation.
Summarise this article
HEV-infection is considered as a major cause of acute hepatitis worldwide.
It has 5 genotypes gt 3 is the dominant in Europe and cause mild and self-limiting symptoms.
Mode of transmission through orofecal route and row meat.
IgM and IgG antibodies against HEV develops because of humoral immune response, and these antibodies stays for years.
Acute HEV gt3 infection can proceed to a chronic course in immunosuppressed patients, which can result in substantial morbidity and mortality.
Even with high levels of anti-HEV IgG antibodies, this case study reveals the development of chronic HEV infection in immunosuppressed patient.
Case presentation:
A 64-year-old man with focal segmental glomerulosclerosis (FSGS) on tacrolimus-based triple drug immunosuppression having history of FSGS recurrence post-transplant treated with plasmapheresis and rituximab, subsequently developed BK viremia then improved now experienced elevated liver enzymes (AST, ALT, and GGT) in November 2016 without clinical symptoms. Despite AST and ALT returning to normal in March 2017, GGT remained high.
On further work up HEV RNA PCR, anti-HEV IgM, and anti-HEV IgG were positive with HEV genotype 3c type. Retrospective blood sample analysis found positive HEV RNA in a sample taken in September 2016 and positive anti-HEV IgG with negative anti-HEV IgM and HEV RNA in a sample taken before the transplant.
Anti-HEV IgM levels increased concurrently with a sharp rise in anti-HEV IgG up until February 2017. In September 2017, the patient underwent an 11-week course of ribavirin treatment before the treatment was stopped due to anemia. In October 2017, liver enzymes returned to normal and plasma HEV RNA became negative.
Discussion:
HEV antibodies are considered to be pivotal to control the infection.
A minimal protective threshold of 2.5 WHO units/mL for anti-HIV antibodies has been proposed. Anti-HEV IgG titers below 6 IU/mL (or 7 WHO units/mL) have been proven to not protect against HEV reinfection. Anti-HEV antibodies in the index patient were 7 IU/ml and were therefore not protective
Ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently need.
In conclusion, this report illustrates that anti-HEV IgG may not be protective in immunosuppressed patients. Suspected cases should undergo HEV NAT testing,
Dietary counseling regarding consumption of raw or undercooked meat (pig) is crucial, and HEV reinfection can be successfully treated with ribavirin.
HEV specific antibodies develop shortly after infection and are thought to confer protection.Authors reported a case of kidney transplant recipient chronic HEV infection despite the presence of high level antibodies. . Upon retrospective analysis of stored serum samples they found that the patient was HEV RNA positive since 7 months but have high level IgG antibody. HEV infection was detected using RT-PCR upon diagnostic evaluation due to increased liver enzymes..Chronic HEV infection was successfully treated with ribavirin.
For clinical practice the following points remain important:
I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide. To date, five humans pathogenic HEV genotypes are known, of which HEVgenotype3(gt3)isthedominantHEVgenotypein Europe.
Recent data demonstrated HEV seroprevalence rates ranging from < 1% up to 52% across Europe.
HEV gt3 is transmitted zoonotically to humans and infections are linked to the consumption of HEV contaminated meat products. In general, HEV infection remains asymptomatic or presents as mild and self-limiting disease. The humoral immune response begins with the rise of anti-HEV IgM antibodies followed by the development of a robust antiHEV IgG response.
Discussion and conclusions
Here, we were able to show a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation. This suggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient. Cases of HEV reinfection leading to chronic courses have been described anecdotally but comprehensive data is lacking at large.
HEV antibodies are considered to be pivotal to control the infection.
Recently, HEV antibodies have been standardized and a minimum protective antibody concentration of 2.5 World Health Organization (WHO) units/mL has been proposed.
However, a definitive protective titer has not been firmly assessed yet. Choi and coworkers recently demonstrated that rhesus macaques with low HEV-IgG titers (< 6 IU/ml) were not protected against HEV reinfection.
As a caveat, HEV serological assays differ in their performance and standardization of antibody assays is under debate, e. g. for rubella.
Interestingly, our patient showed a rapid rise in anti-HEV IgG which was followed by an anti-HEV IgM response shortly after. This pattern is typical for a booster immune response and has been demonstrated for HEV in vivo.
However, despite the rapid anti-HEV IgG response this did not lead to clearance of HEV RNA from the blood in our patient. This further supports the notion of a limited protective humoral immune response.
Interestingly, the rituximab induced B cell depletion might have influenced the development of HEV antibodies in our patient, but anti-HEV IgG levels did never fall below the cut-off of the assay.
Beyond the humoral response and the immunosuppressive therapy chronic HEV infection has been associated with an impaired HEV-specific T-cell response in transplant patients
However, the T-cell mediated immune response remains largely unclear in HEV infection and deserves further study. We were able to show that the HEV-specific CD8+ Tcell response in chronic HEV patients was diminished in comparison to the acute disease course but was partially restored after ribavirin therapy (own unpublished data).
For clinical practice the following points remain
important:
I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
V. In conclusion, we were able to identify a patient with HEV reinfection who developed a chronic course which was successfully treated with ribavirin. The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
Summarize this article
Background
– HEV is a major cause of hepatitis worldwide, transmitted through feco-oral route and consumption of contaminated meat products
– Of the 5 genotypes, Genotype-3 is commonest in Europe
– HEV infection remains asymptomatic or presents as mild and self-limiting disease.
– In immunocompromised patients, acute infection by HEV genotype 3 can progress to chronicity (anti-HEV Abs detectable >6months), associated with high morbidity and mortality.
– Immune response starts with anti-HEV IgM antibodies followed by anti-HEV IgG, which declines over time but may remain detectable for years, and whether HEV specific antibodies confer any protection is controversial.
Case presentation
– 64years male FSGS – ESRD patient, underwent kidney transplant in April 2016, on triple drug regimen
– June 2016: recurrent FSGS treated with rituximab (750mgx2), 26 plasma exchange and 10gm IVIg (for hypogammaglobulinemia).
– July 2016: due to intense IS, he developed BKV viremia (383,500 copies/mL) à responded to reduced IS (prednisone tapered to 10mg/d, MMF reduced to 250mg BD) à BKV resolved (<1000 copies/mL) from Oct 2016 onwards; then MMF was increased to 500mg BD; also, FSGS resolved until Oct 2016.
– November 2016: elevated liver enzymes: AST 62, ALT 81, GGT 276, with a normal liver ultrasound
– March 2017: he was doing well, on tacrolimus 1mg BD, trough level 5-8ng/mL, MMF 500mg BD, prednisone 7.5mg/d; normal AST (44) & ALT (45), but elevated GGT (215) and liver ultrasound. HCV RNA was negative, HEV RNA, anti-HEV IgM and IgG positive – indicating an active HEV infection.
– retrospective analysis of stored plasma samples revealed positive HEV RNA since September 2016 indicating chronic HEV infection
– stored pre-transplant plasma samples were positive for anti-HEV IgG but negative for anti-HEV IgM and HEV RNA indicating resolved HEV infection before transplantation
– there was a rapid rise in anti-HEV IgG after HEV RNA was first detected in September 2016 but anti-HEV IgM remained negative
– February 2017: positive anti-HEV IgM and IgG à indicated reactivation of active HEV infection
– September 2017: Ribavirin therapy (200mg 5 doses daily) initiated; liver enzymes partially elevated (AST 77, ALT 78, GGT 226); but therapy was stopped at 11 weeks due to severe anaemia.
– October 2017: plasma HEV RNA became negative and remained negative throughout with normal liver enzymes, indicating successful response to therapy (SVR).
Discussion
– mode of HEV infection acquisition in this patient remains unknown
– could be due to an HEV-contaminated transplant organ, contaminated blood products, consumption of contaminated food post-transplant
– The patient had chronic HEV infection in spite of detectable anti-HEV IgG before and after kidney transplantation
– Anti-HEV-IgG Abs might control HEV infection, and a minimum protective concentration of 2.5units/mL has been proposed.
– Anti-HEV Abs did not confer protection in this patient, resulting in a chronic HEV infection
– Rituximab induced B cell depletion might have contributed to the reinfection in spite of the presence of Anti-HEV Abs.
– Immunosuppressive therapy affecting humoral response can result in a decrease in the anti-HEV IgG titres after transplantation
– Immunosuppressive therapy impairs HEV-specific T-cell response in transplant recipients. Tacrolimus is thought to promote infection of hepatocytes with HEV, MMF inhibits HEV replication, while steroids showed no effect at all
– this index patient most likely had HEV reactivation, since HEV RNA remained undetectable before and shortly after transplantation
– few cases of HEV reactivation have been described in literature
– chronic HEV infection can result in liver cirrhosis and liver failure
– this patient responded well to ribavirin, although the therapy discontinued due to anaemia
– Ribavirin is currently the only drug available for treatment of HEV infection in transplant recipients
– Peg-interferon has antiviral activity against HEV but can’t be used due to high risk of rejection
– Sofosbuvir, a proteosome inhibitor of HCV, may be effective but more studies are needed on its use in HEV
Conclusion
– presence of anti-HEV IgG may not confer protection this therefore limits the significance of testing anti-HEV IgG pre-transplant/ before initiating immunosuppressive therapy
– in patients with elevated liver enzymes, screen for HEV infection regardless of the anti-HEV IgG status before immunosuppression
– NAT (nucleic acid testing) is useful to diagnose HEV infection in immunocompromised patients
– counsel/ educate patients at risk for chronic HEV infection about consumption of raw/ undercooked pork products
– role of T-cell mediated and humoral immune response in HEV reinfection requires further research
Background:
HEV-infection is considered as a major cause of acute hepatitis worldwide.
It has 5 genotypes gt 3 is the dominant in Europe and cause mild and self-limiting symptoms.
Mode of transmission through orofecal route and row meat.
IgM and IgG antibodies against HEV develops because of humoral immune response, and these antibodies stays for years.
Acute HEV gt3 infection can proceed to a chronic course in immunosuppressed patients, which can result in substantial morbidity and mortality.
Even with high levels of anti-HEV IgG antibodies, this case study reveals the development of chronic HEV infection in immunosuppressed patient.
Case presentation:
A 64-year-old man with focal segmental glomerulosclerosis (FSGS) on tacrolimus-based triple drug immunosuppression having history of FSGS recurrence post-transplant treated with plasmapheresis and rituximab, subsequently developed BK viremia then improved now experienced elevated liver enzymes (AST, ALT, and GGT) in November 2016 without clinical symptoms. Despite AST and ALT returning to normal in March 2017, GGT remained high.
On further work up HEV RNA PCR, anti-HEV IgM, and anti-HEV IgG were positive with HEV genotype 3c type. Retrospective blood sample analysis found positive HEV RNA in a sample taken in September 2016 and positive anti-HEV IgG with negative anti-HEV IgM and HEV RNA in a sample taken before the transplant.
Anti-HEV IgM levels increased concurrently with a sharp rise in anti-HEV IgG up until February 2017. In September 2017, the patient underwent an 11-week course of ribavirin treatment before the treatment was stopped due to anemia. In October 2017, liver enzymes returned to normal and plasma HEV RNA became negative.
Discussion:
HEV antibodies are considered to be pivotal to control the infection.
A minimal protective threshold of 2.5 WHO units/mL for anti-HIV antibodies has been proposed. Anti-HEV IgG titers below 6 IU/mL (or 7 WHO units/mL) have been proven to not protect against HEV reinfection. Anti-HEV antibodies in the index patient were 7 IU/ml and were therefore not protective
Ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently need.
In conclusion, this report illustrates that anti-HEV IgG may not be protective in immunosuppressed patients. Suspected cases should undergo HEV NAT testing,
Dietary counseling regarding consumption of raw or undercooked meat (pig) is crucial, and HEV reinfection can be successfully treated with ribavirin.
Background
Case presentation
A 64-year-old man with focal segmental glomerulosclerosis (FSGS) on tacrolimus-based triple drug immunosuppression having past history of FSGS recurrence post-transplant treated with plasmapheresis and rituximab, subsequently developed BK viremia then improved now experienced elevated liver enzymes (AST, ALT, and GGT) in November 2016 without clinical symptoms. Despite AST and ALT returning to normal in March 2017, GGT remained high.
On further work up HEV RNA PCR, anti-HEV IgM, and anti-HEV IgG were positive with HEV genotype 3c type. Retrospective blood sample analysis found positive HEV RNA in a sample taken in September 2016 and positive anti-HEV IgG with negative anti-HEV IgM and HEV RNA in a sample taken before the transplant.
Anti-HEV IgM levels increased concurrently with a sharp rise in anti-HEV IgG up until February 2017. In September 2017, the patient underwent an 11-week course of ribavirin treatment before the treatment was stopped due to anemia. In October 2017, liver enzymes returned to normal and plasma HEV RNA became negative.
Discussion
IV. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
Summarise this article
Background
– HEV is a major cause of hepatitis worldwide
– 5 genotypes have been described
– transmission is through consumption of contaminated meat products
– HEV specific antibodies develop after HEV infection and are thought to confer protection, although this remains controversial
– the minimum protective HEV Ab concentration is yet to be established
– HEV infection presents as a mild self-limiting disease or remains asymptomatic
– anti-HEV IgM Abs are usually the first to rise followed by anti-HEV IgG Abs
– anti-HEV IgG Ab levels decline over time but may remain detectable for years
– among immunocompromised patients, active HEV genotype 3 infection can progress to a chronic infection with HEV Abs remaining detectable for >6months
– it is associated with high morbidity and mortality
Case presentation
– 64yo man, FSGS, kidney transplantation in April 2016
– immunosuppressive regimen: tacrolimus, mycophenolate mofetil, prednisone
– June 2016 had FSGS recurrence: received rituximab 750mg twice, therapeutic plasma exchange (TPE) 26 times with albumin and FFPs as replacement fluid
– June 2016 had hypogammaglobulinemia: given IVIG 10g
– July 2016 had BKV viremia (383,500 copies/mL): prednisone was tapered to 10mg/d, MMF reduced to 250mg BD
– from October 2016 onwards, plasma BKV viremia remained <1000 copies/mL and MMF was increased to 500mg BD
– the recurrent FSGS resolved until October 2016
– November 2016 had elevated liver enzymes: AST 62, ALT 81, GGT 276, with a normal liver ultrasound
– March 2017, doing well on tacrolimus 1mg BD, trough level 5-8ng/mL, MMF 500mg BD, prednisone 7.5mg/d, normal AST 44, normal ALT 45, elevated GGT 215, with a normal abdominal ultrasound, HCV RNA negative, HEV RNA positive indicating an active HEV infection, anti-HEV IgM and IgG were also positive
– retrospective analysis of stored plasma samples revealed positive HEV RNA since September 2016 indicating chronic HEV infection
– stored pre-transplant plasma samples were positive for anti-HEV IgG but negative for anti-HEV IgM and HEV RNA indicating resolved HEV infection before transplantation
– there was a rapid rise in anti-HEV IgG after HEV RNA was first detected in September 2016 but anti-HEV IgM remained negative
– February 2017: positive anti-HEV IgM, positive anti-HEV IgG
– September 2017: initiated on ribavirin 200mg 5 doses daily; AST 77, ALT 78, GGT 226, was on ribavirin for 11 weeks, therapy was stopped due to anaemia
– October 2017: negative plasma HEV RNA (for the first time), it remained negative indicating successful response to therapy, liver enzymes normalized
– mode of HEV infection acquisition in this patient remains unknown but could be due to an HEV-contaminated transplant organ, contaminated blood products, consumption of contaminated food post-transplant
Discussion
– this patient had chronic HEV infection in spite of detectable anti-HEV IgG before and after kidney transplantation suggesting HEV reinfection
– this indicates that the HEV Abs did not confer protection in this particular patient resulting in a chronic HEV infection
– HEV Abs are key in controlling the infection
– a minimum protective antibody concentration of 2.5units/mL has been proposed
– the rituximab induced B cell depletion might have contributed to the reinfection in spite of the presence of HEV Abs
– immunosuppressive therapy affects the humoral response and this can result in a decrease in the anti-HEV IgG titers shortly after transplantation
– tacrolimus is thought to promote infection of hepatocytes with HEV, MMF inhibits HEV replication, while steroids showed no effect at all
– immunosuppressive therapy impairs HEV-specific T-cell response in transplant recipients
– few cases of HEV reactivation have described in literature
– most likely this patient had HEV reactivation since HEV RNA remained undetectable before and shortly after transplantation
– chronic HEV infection can result in liver cirrhosis and liver failure
– this patient responded well to ribavirin unfortunately he developed anaemia warranting discontinuation of the antiviral therapy
– ribavirin is currently the only drug that is available for treatment of HEV infection
– pegylated interferon has antiviral activity against HEV but it cannot be used in HSCT or SOT recipients due to a high risk of rejection
– sofosbuvir, a proteosome inhibitor of HCV, may be effective but more studies are needed to support its use
Conclusion
– presence of anti-HEV IgG may not confer protection this therefore limits the significance of testing anti-HEV IgG pre-transplant/ before initiating immunosuppressive therapy
– in patients with elevated liver enzymes screen for HEV infection regardless of the anti-HEV IgG status before immunosuppression
– use NAT (nucleic acid testing) to diagnose HEV infection in immunocompromised patients
– counsel/ educate patients at risk for chronic HEV infection about consumption of raw/ undercooked pork products
– role of T-cell mediated and humoral immune response in HEV reinfection requires further research
Background
· Five human pathogenic HEV genotypes are known, of which HEV genotype 3 is the commonest in Europe.
· HEV infection remains asymptomatic or presents as mild and self-limiting disease.
· Response started with anti-HEV IgM antibodies followed by antiHEV IgG, which declines over time but may remain detectable for years.
· In immunosuppressed patients, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates.
Case presentation
· A 64-year-old man with a history of FSGS, recurrence of FSGS post transplant, given rituximab 750 mg twice and therapeutic plasma exchange, and maintained on Tacrolimus, MMF, and prednisone.
· post-transplantation course showed BKV viremia three months after transplantation, so MMF was reduced to a dose of 250 mg twice daily.
· BKV viremia remained below 1000 copies/mL, so MMF was increased to 500 mg twice daily.
· After that routine lab found: AST 62 U/L, ALT 81 U/L, and γ-GT 276 U/ L.
· Ultrasound of the liver showed no pathological findings.
· Testing for hepatitis C virus RNA was negative, however, HEV RNA was detected using RT-PCR.
· Concomitantly anti-HEV IgM and IgG using ELISA were positive.
· Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months indicating chronic HEV infection
· Anti-HEV IgG showed a rapid rise after HEV RNA was first detectable, while anti-HEV IgM remained negative.
· Ribavirin (200 mg, 5 doses daily) was given for 11- weeks and was stopped due to anemia.
· HEV RNA in plasma became negative, and Liver enzymes normalized.
Discussion and conclusions
· This is a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation.
· Testing for anti-HEV IgG before the start of immunosuppressive regimens has no value.
· Testing for HEV infection indicated for recipients with elevated liver enzymes.
· In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
· Counseling patients at risk for chronic HEV infection to stop eating raw pig products seems.
Background
● Hepatitis E virus (HEV) infection is a major cause of acute hepatitis worldwide.
● Five HEV genotypes are known
● prevalence ranging from < 1% up to 52%
● Transmitted to humans by HEV contaminated meat products.
● HEV infection is asymptomatic or mild and self-limiting disease.
● In immunosuppressed patients acute HEV gt3 infection can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality
● Here a case of a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG pre- and posttransplant
Case presentation
☆ A 64-year-old man with FSGS
☆ kidney transplantation
☆ IS medication ( tac, MMF, pred )
☆ He received RTX 750 mg 2 doses besides PE for treatment recurrence FSGS
☆ He had BKV viremia three months after transplantation (DNA concentration 383,500 copies/mL).
☆ IS ( pred and MMF ) have reduced and viremia remained below 1000 copies/mL plasma then mycophenolate mofetil was
increased to 500 mg twice daily.
☆ Due to hypogammaglobulinemia IVIG (10 g) were given
☆ Routine laboratory testing revealed elevated AST, ALT and γ-GT
☆ Liver Ultrasound is normal
☆ Testing for hepatitis C virus RNA was negative
☆ HEV RNA was detected indicating active HEV infection.
☆ Anti-HEV IgM and IgG were positive.
☆ stored plasma samples taken before kidney transplantation were positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before transplantation
☆ A rise in HEV IgG occurred parallel to the increase seen with the Mikrogen ELISA.
☆ Yreatment of ribavirin (200 mg, 5 doses daily) was initiated for 11-week then stopped due to anemia.
☆ HEV RNA in plasma was negative and remained negative indicating successful therapy.
☆ Liver enzymes returned back to normal
☆ The mode of acquisition of HEV infection in this patient remains unclear but could be related to HEV- contaminated blood products, an HEV-contaminated transplant organ, or food uptake after transplantation.
Discussion and conclusions
● A case of chronic HEV infection despite the presence of anti-HEV IgG before and after kidney transplantation.
● HEV antibodies did not give patient protection
● low HEV-IgG titers (< 7 IU/ml) were not protected against HEV reinfection
● Despite rapid anti-HEV IgG response it did not lead to clearance of HEV RNA from the blood
● Functional B cells are instrumental to control the infection and antibodies might not be the only correlate of protection
● A nti-HEV IgG titers decreased shortly after transplantation suggestion an influence of the immunosuppressive therapy on the humoral immune response.
● Tacr promoted the infection of liver cells with HEV whereas MMF inhibited HEV replication and steroids showed no effect
● Chronic HEV infection impairs HEV-specific T-cell response in transplant patients
● Ribavirin is the only drug available for treatment of HEV infection
● Pegylated interferon-alfa has antiviral activity against HEV but cannot be used in transplants due to a high risk of rejection.
● Important clinical practice points :
I. The presence of anti-HEV IgG may not be
protective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/undercooked pig products seems advisable.
V. In conclusion, we were able to identify a patient with HEV reinfection who developed a chronic course which was successfully treated with ribavirin.
HEV after KIDNEY TRANSPLANTATION
HEV gt3 IS COMMON GENOTYPE
ANTI HEV IM AND then IG antibodies are developed in response to acute HEV infection
HEV transmission is through contaminated meat
Antibodies are thought to protect aging infection but this fact is not proven yet
index case represent acute HEV infection in post transplant scenario inspite of ANTI HEV antibody
so monitoring HEV RNA in serum in indicated cases( symptomatic and raised liver enzymes ) is MUST
index case had HEV RNA before the transplant indicating chronic HEV infection and antibodies were not neutralizing and were not effective.
Treatment of index case
ribavarin 200 mg 5 times a day , 11 weeks
stopped due to anaemia , commonest AE
conclusion
case of chronic HEV in spite of anti HEV IG
this suggest REINFECTION with HEV
Protective level of 2.4 WHO units /ml was proposed BUT it is not clear yet
IS drugs reduces the level of antibody post transplant
IS drugs may alter the chances of HEV to enter the liver cells like TACROLIMUS may enhance the entry of virus into the cell
. Clinical work-up upon increased liver enzymes
should include testing for HEV infection
irrespective of the anti-HEV IgG status before
immunosuppression
*This study reported a patient who developed chronic HEV infection shortly PKT despite the presence of high anti-HEV IgG pre- and post-transplantation and described and characterized the HEV-specific antibody response over time.
*Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
*To date, five human pathogenic HEV genotypes are known, of which HEV genotype 3 (gt3) is the dominant HEV genotype in Europe.
* Recent data demonstrated HEV seroprevalence rates ranging from < 1% up to 52% across Europe. *HEV infection remains asymptomatic or presents as mild and self-limiting disease.
*The humoral immune response begins with the rise of anti-HEV IgM antibodies followed by the development of a robust anti- HEV IgG response.
*The anti-HEV IgG antibody concentration then slowly declines over time but may remain detectable for years.
*In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates, and the HEV specific antibody response is variable or lacking at large.
Case presentation:
*The study report an immunocompromised patient who developed chronic HEV infection despite the
presence of high level antibodies.
*The HEV infection was detected using RT-PCR upon diagnostic evaluation due to increased liver enzymes.
*Upon retrospective analysis of stored serum samples they found that the patient was HEV RNA positive since 7 months. Chronic HEV infection was successfully treated with ribavirin.
# Discussion:
*The study showed HEV reinfection and indicates that HEV antibodies did not confer protection in this patient.
*HEV antibodies are considered to be pivotal to control the infection.
*Concentration of 2.5 (WHO) units/mL has been proposed. However, a definitive protective
titer has not been firmly assessed yet
# For clinical practice the following points remain important:
I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti- HEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
V. In conclusion, we were able to identify a patient with HEV reinfection who developed a chronic
course which was successfully treated with ribavirin. The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
# Conclusions:
*The patient suffered from a chronic course of HEV infection, which was successfully treated with ribavirin.
*The study case underlines the importance of RT-PCR for HEV diagnostics in immunosuppressed patients and supports the notion that HEV antibodies do not confer universal protection.
*Counseling patients at risk for chronic HEV infection seems advisable.
*The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide. To date, five human pathogenic HEV genotypes are known, of which HEV genotype 3 (gt3) is the dominant HEV genotype in Europe.
The humoral immune response begins with the rise of anti-HEV IgM antibodies followed by the development of a robust antiHEV IgG response.
The anti-HEV IgG antibody concentration then slowly declines over time but may remain detectable for years.
In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality rates.
For clinical practice the following points remain important:
I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
V. In conclusion, we were able to identify a patient with HEV reinfection who developed a chronic course which was successfully treated with ribavirin. The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
Background
HEV is a zoonotic disease with orofeack rate transmission.
This case study proves that in the case of post-RTX and immunosuppressed individuals, we may have reinfection of HEV despite being immunised, but this patient adding to the IS that he is taking, he did PEX and IV rituximab for his FSGN disease, which will affect his humoral immunity as well. This patient, despite having Anti HEVAb IgG, failed to confer immunity and protect himself and developed high ALLT and GGT with no finding in the US abdomen.
This type of infection has happened as reinfection evidenced by the reappearance of Anti HEVAb IgM level in the serum.
Background
Case presentation
A 64-year-old man with focal segmental glomerulosclerosis (FSGS) on tacrolimus-based triple drug immunosuppression having past history of FSGS recurrence post-transplant treated with plasmapheresis and rituximab, subsequently developed BK viremia then improved now experienced elevated liver enzymes (AST, ALT, and GGT) in November 2016 without clinical symptoms. Despite AST and ALT returning to normal in March 2017, GGT remained high.
On further work up HEV RNA PCR, anti-HEV IgM, and anti-HEV IgG were positive with HEV genotype 3c type. Retrospective blood sample analysis found positive HEV RNA in a sample taken in September 2016 and positive anti-HEV IgG with negative anti-HEV IgM and HEV RNA in a sample taken before the transplant.
Anti-HEV IgM levels increased concurrently with a sharp rise in anti-HEV IgG up until February 2017. In September 2017, the patient underwent an 11-week course of ribavirin treatment before the treatment was stopped due to anemia. In October 2017, liver enzymes returned to normal and plasma HEV RNA became negative.
Discussion
Chronic hepatitis E after kidney transplantation with antibody response suggestive of reinfection: a case report
A 64-year-old
The primary disease for his ESRD was FSGS
Kidney transplantation April 2016
Recurrent FSGS post-transplant (June 2016) treated with: Rituximab, TPE x 26 times
Complicated with BK viremia
Presented with worsening derangement of liver enzyme
HCV RNA negative
HEV RT-PCR detected (since > six months earlier) – before the transplant was negative (IgM negative) with positive IgG
anti-HEV IgM detected
anti-HEV IgG detected
Treatment with Ribavarin 200 mg 5 times a day for 11 weeks
Outcome: Negative HEV RNA and normalisation of liver enzyme
Conclusion: anti-HEV did not confer protection in this patient; perhaps it is related to the number of antibodies.This is partly contributed by anti-CD20 therapy.
CHRONIC HEP E AFTER KIDNEY TRANSPLANTATION WITH AN ANTIBODY RESPONSE SUGGESTIVE OF REINFECTION;A CASE REPORT.
BACKGROUND
CASE PRESENTATION.
DISCUSSION AND CONCLUSION.
Background
· HEV infection is a major cause of acute hepatitis worldwide, with five human pathogenic genotypes known.
· HEV genotype 3 (gt3) is the dominant genotype in Europe, with seroprevalence rates ranging from < 1% up to 52%.
· In general, HEV infection remains asymptomatic or self-limiting, but in immunosuppressed patients, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates.
· This study reports a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG pre- and post-transplantation and describes and characterizes the HEV-specific antibody response over time.
Method:
· This case study describes a patient with immunosuppression who contracted persistent HEV infection despite having high levels of antibodies.
· Due to elevated liver enzymes, HEV infection was discovered using RT-PCR after the diagnostic examination.
· Retrospective examination of serum samples that had been preserved revealed that the patient had been HEV RNA positive for 7 months.
· Ribavirin was used to successfully treat a chronic HEV infection.
Discussion and conclusions
· HEV infection despite detectable anti-HEV IgG before and after kidney transplantation, suggesting HEV reinfection.
· Immunocompromised individuals with low anti-HEV IgG levels are not protected against reinfection.
· While anti-HEV IgG levels did not decrease below the cut-off due to rituximab-induced B cell depletion, this suggests that functioning B cells are not the main correlate of protection.
· The epitope-specific analysis of the immune response showed antibodies directed against ORF2, paralleled by an increase in anti-HEV IgG.
· Immunosuppressive therapies may influence the humoral immune response and HEV replication cycle, as demonstrated by Wang and colleagues.
· Chronic HEV infection has been associated with an impaired HEV-specific T-cell response, which needs further study.
· We did not detect HEV RNA before and shortly after transplantation, suggesting no reactivation.
· Ribavirin is the only drug available for HEV infection, but novel treatment strategies are needed, such as sofosbuvir and interferon alfa.
· Testing for anti-HEV IgG before immunosuppression and counseling patients at risk for chronic HEV infection is important for clinical practice..
Conclusion:
· In addition to demonstrating the value of RT-PCR for HEV diagnoses in immunocompromised individuals, this example demonstrates that HEV antibodies do not provide complete protection from HEV infection.
· It would appear prudent to counsel individuals who are susceptible to persistent HEV infection.
· More research is needed to understand the function of the humoral and T-cell-mediated immune response in HEV reinfection patients.
This is a case report of A 64-year-old man, had kidney transplantation in April 2016. He is maintained on tacrolimus, mycophenolate mofetil and prednisone. In addition, he received rituximab twice and therapeutic plasma exchange (26 times), due to recurrence of focal segmental glomerulosclerosis. His post-transplantation course showed BKV viremia that was treated with reduced immune suppression and Igs.
in November 2016, routine laboratory testing revealed elevated AST, ALT and γ-GT (276 U/ L. Ultrasound of the liver was normal.
Testing for hepatitis C virus RNA was negative, however, HEV RNA was detected using RT-PCR. Concomitantly anti-HEV IgM (71.5 AU/mL) and IgG (149 AU/mL) using ELISA were positive. Retrospective analysis of stored plasma samples showed positive HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection. analysis of HEV RNA demonstrated an HEV genotype 3c. Interestingly, stored plasma samples taken before kidney transplantation were positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before transplantation.
To better appreciate the level of HEV IgG antibodies, a quantitative HEV ELISA was used, which was calibrated against the WHO standard and expresses HEV IgG in IU/ml. Early samples tested HEV IgG borderline (April 2016) and negative (August 2016).
Patient was started treatment with ribavirin (200 mg, 5 doses daily), for 11- weeks course and therapy was stopped due to anemia. HEV RNA in plasma was first negative in October 2017 and remained negative indicating successful therapy. Liver enzymes returned back to normal range.
Since earlier samples were negative, the mode of acquisition of HEV infection in this patient remains unclear but could be related to HEV contaminated blood products, an HEV-contaminated transplant organ, or food uptake after transplantation. Furthermore, the rituximab induced B cell depletion might have influenced the development of HEV antibodies in this patient, but anti-HEV IgG levels did never fall below the cut-off of the assay. Thus, impaired B cells in our immunosuppressed patient might have contributed to reinfection despite the presence of HEV antibodies.
Though this patient had detectable anti-HEV IgG before and after kidney transplantation, yet HEV reinfection had occur and indicates that HEV antibodies did not confer protection in this patient.
Of note, in immunocompromised patients a French study found that a low anti-HEV IgG of < 7 WHO units/mL did not protect against reinfection.
Treatment with ribavirin was successful in this patient but anemia as well-known side effect of ribavirin led to the discontinuation of antiviral therapy. Currently, ribavirin is the only drug available for treatment of HEV infection. Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
For clinical practice the following points remain important:
I. The presence of anti-HEV IgG may not be protective.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
Summary
HEV seroprevalence rates ranging from < 1% up to 52% in Europe. HEV gt3 is transmitted zoonotically to humans and infections are linked to the consumption of HEV contaminated meat products. The humoral immune response begins with the rise of anti-HEV IgM antibodies followed by the development of a robust anti HEV IgG response. The anti-HEV IgG antibody concentration then slowly declines over time but may remain detectable for years. In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates.
Here, in this case report a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG pre- and post-transplantation.
In this case study a 64-year gentleman underwent kidney transplantation in April 2016, end stage kidney disease was secondary to focal segmental glomerulosclerosis. Immunosuppressive medication included tacrolimus, mycophenolate mofetil and prednisone. In addition, he received rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma. He has BK viremia treated by reduction of immunosuppressive medications (MMF), and Intravenous immunoglobulins (10 g) were given on June 2016 due to hypogammaglobulinemia. In November 2016, found to have modest elevation of liver function ALT 81, AST and gamma GT 276.HEV RNA was detected using RT-PCR. Concomitantly anti-HEV IgM and IgG using ELISA were positive.
Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection.
Discussion
Choi and coworkers demonstrated that rhesus macaques with low HEV-IgG titers (< 6 IU/ml) were not protected against HEV reinfection. Despite the rapid anti-HEV IgG response this did not lead to clearance of HEV RNA from the blood in our patient.
The rituximab induced B cell depletion might have influenced the development of HEV antibodies in this patient but in this case anti-HEV IgG levels did never fall below the cut-off of the assay.
Impaired B cells in our immunosuppressed patient might have contributed to reinfection despite the presence of HEV antibodies.
Beyond the humoral response and the immunosuppressive therapy chronic HEV infection has been associated with an impaired HEV-specific T-cell response in transplant patients
At the moment ribavirin is the only drug available for treatment of HEV infection and new treatment strategies are urgently needed. Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
Conclusion
In this HEV reinfection case, who developed a chronic course which was successfully treated with ribavirin in spite of having HEV Igg. The role of the humoral and T-cell mediated immune response in cases of HEV reinfection is inconclusive and needs further study.
Summarise this article
Background
-Hepatitis E virus (HEV) infection is increasingly recognized
as a major cause of acute hepatitis worldwide. HEV genotype 3 (gt3) is the dominant HEV genotype in Europe.
-HEV gt3 is transmitted zoonotically to humans and infections
are linked to the consumption of HEV contaminated meat
products.
-It remains asymptomatic or presents as mild and self-limiting disease. -The humoral immune response begins with the rise of anti-HEV IgM
antibodies followed by the development of a robust anti- HEV IgG response .
Case report
-A 64-year-old man with a history of focal segmental glomerulosclerosis
underwent kidney transplantation in April 2016 on tacrolimus, mycophenolate mofetil and prednisone. His post-transplantation course showed BKV viraemia ,elevated liver enzymes chronic HEV infection.
– This suggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient.
-Impaired B cells in our immunosuppressed patient might have contributed to reinfection despite the presence of HEV antibodies.
– Anti-HEV IgG titers decreased shortly after transplantation suggestion an influence of the immunosuppressive therapy on the humoral immune response.
-Immunosuppressive therapies might interfere with the HEV replication cycle . Tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication
and steroids showed no effect at all .
-This patient developed chronic HEV infection which can lead to rapidly developing cirrhosis and liver failure . Ribavirin is the only drug available for treatment of HEV infection and novel treatment
strategies are urgently needed.
For clinical practice the following points remain important:
I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti- HEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before
immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
HEV infection remains asymptomatic or presents as mild and self-limiting diseaseز Of note, no definitive minimum protective HEV antibody concentration has been established yet.
In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality rates.
This article presented a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation. This suggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient
Currently, ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently needed. Pegylated interferon- alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
Background :
HEV infection is a major cause of acute hepatitis worldwide, with five human pathogenic genotypes known. HEV genotype 3 (gt3) is the dominant genotype in Europe .
The humoral immune response begins with the rise of anti-HEV IgM antibodies followed by the development of a robust anti HEV IgG response.
In immunosuppressed patients, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates, but the HEV specific antibody response is variable or lacking at large.
case report :
A 64-year-old man with a history of focal segmental glomerulosclerosis underwent kidney transplantation in April 2016.
After transplantation his immunosuppressive regimen included tacrolimus, mycophenolate mofetil and prednisone he was given rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as replacement fluid for recurrent FSGS .
His post-transplantation course showed BKV viremia
Three months after transplantation he developed BKV viremia for which reduction of immunosuppression was done .
Ultrasound of the liver done 6 months after transplantation because of high liver enzymes which showed no pathological findings .other screening of HBV,HCV were negative . HEV RNA was found to be positive in retrospective samples over the last 7 months which is consistent with chronic HEV infection.
Anti-HEV IgG showed a rapid rise after HEV RNA was first detectable in September 2016 and became positive in February 2017.
The patient received an 11-week course of ribavirin (off-label use) and therapy was stopped due to anemia.
HEV RNA in plasma was negative in October 2017 and remained negative indicating successful therapy.
The mode of transmission of HEV infection was unclear in this patient, he had no recent travel and no information on food consumption was possible
Discussion :
This study showed a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation.
HEV antibodies are considered to be pivotal to control the infection, and a minimum protective antibody concentration of 2.5 World Health Organization (WHO) units/mL has been proposed. Despite the rapid anti-heV IgG response, this did not lead to clearance of HEV RNA from the blood in the patient, suggesting a limited protective humoral response. Immunosuppressive therapies may also interfere with the HEV replication cycle.
The CD8+ Tcell response in chronic HEV patients was diminished in comparison to the acute disease course, but was partially restored after ribavirin therapy which is the only available treatment so urgent novel treatment strategies are needed .
Conclusion :
HEV infection should be suspected for any unexplained elevated liver enzymes in immunosuppressed patients . , diagnosing HEV infection using nucleic acid testing, counseling patients at risk for chronic HEV infection regarding the consumption of raw/undercooked pig products. The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
Introduction
HEV recently consider the most common cause of acute hepatitis worldwide with good immune response and self-limiting viral infection without treatment however in immunosuppressed patients there is growing evidence supporting the reactivation of HEV and causes chronic HEV infection with fast progression to liver cirrhosis up to 10%. If left untreated, there are 5 genotypes of HEV genotype 3 is more predominant in Europe with quite variable prevalence from < 1 to more > than 50% in some parts. HEV genotype 3 (gt3) is mainly transmitted through the ingestion of contaminated raw animal meat from pigs. Can be asymptomatic but there is an increased risk of reactivation after SOT and progress to chronic HEV infection with the only clue being the unexplained elevated liver enzymes despite adequate HEV IgG level. this case report of Chronic hepatitis E after kidney transplantation despite good antibody response suggestive of reinfection indicates that HEV antibodies did not confer protection in this patient and addresses the importance of RT-PCR molecular testing for the diagnosis of HEV infection and emphasizes that HEV antibodies alone are not protective against reactivation of HEV in immunocompromised patients after SOT
No clear cut-off value of anti-HEV IgG level to be considered protective however some studies suggest value < 7 IU is not protective against HEV reactivation or reinfection in general the
The mode of transmission of HEV is either through blood and blood product contamination or through transplant organ contamination, and ingestion of raw contaminated meat.
Impaired B cells with rituximab might have contributed to reinfection despite the presence of HEV antibodies. Immunosuppression therapy after SOT as reported by one study that tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect at all.
Currently, ribavirin is the only drug available for the treatment of HEV infection with the risk of hemolytic anemia, novel treatment is needed so far alternatives like sobovivor in resistance cases have been studied
Take home message from this case report
HEV re-infection or reactivation should be considered after SOT with persistent unexplained elevated liver enzymes
HEV IgG antibodies level is of limited value in the diagnosis and protection against HEV reinfection. and we need HEV RNA (NAT) In immunosuppressed patients, for confirmation of the diagnosis
Education of the patients with proper counseling about the avoidance of raw meat or undercooked pig products.
After reviewing this case report i just asked our gastero-team about the epidemiology of HEV in our region and whats our practice about the screen , in our center we do HEVserologyy only and we don’t have HEV RNA as it’s under the request of exterinalitemm
This is a case report of re-infection of Hepatitis E virus which did not resolve spontaneously post transplant and became chronic
Introduction:
HEV is becoming one of the common causes of hepatitis. The seroprevalence of HEV in Europe ranges from less than 1% to 52%. There are 5 genotypes with genotype 3 being the most common in Europe. It is transmitted by consuming contaminated meat. Normally HEV infection is asymptomatic and self limiting but can result in fulminant hepatitis in pregnant women. The humoral immune response manages the infection with a rise in IgM followed by IgG but the IgG titers wane over time. In the immunocompromised patient, the clearance of the virus is affected and can lead to chronicity
Case presentation
A 64 year old male with ESKD secondary to FSGS who underwent kidney transplant in April 2016 and was on triple immunosuppression with tacrolimus, MMF and prednisone. He received plasma exchange and rituximab post transplant due to recurrence of FSGS. He also received IVIG due to hypogamaglobulinemia. On routine liver function test, he was found to have elevated transaminases with a normal liver USS. Further investigations revealed HEV infection. Both HEV IgM and IgG titers were high. retrospective analysis of serum samples from September 2016 showed the presence of HEV RNA. Genotyping revealed it to be genotype 3c. The stored plasma pre-transplantation showed elevated titers of IgG and no titers of IgM and no detectable HEV RNA suggesting prior HEV infection. he was started on ribavirin 200 mg five times daily for 11 weeks. the treatment was stopped due to the development of anemia.
Discussion
This case shows re-infection with HEV with no protection conferred by the IgG Ab. HEV Ab are considered vital to prevent re-infection. Recently HEV Ab have been standardized and a minimum protective Ab concentration of 2.5 WHO units/ml have been proposed. However, a definitive protective titer has not been conclusively assessed as yet. The patient had a rapid rise in the anti HEV IgG titers followed by a rise in the anti HEV IgM titers indicating a booster response. However, it was not sufficient to clear the virus. The impaired B cells due to immunosuppression could have been responsible for the lack of clearance. The anti-HEV IgG titers decreased shortly post-transplantation suggesting an influence of immunosuppression on the humoral response. Wang et al have shown that tacrolimus promoted the infection of liver cells by HEV whereas MMF inhibited HEV replication.
Currently ribavirin is the only drug available for the treatment of HEV infection. Pegylated interferon alpha has activity against HEV but cannot be used in HSCT or SOT as it can trigger rejection
It is important to note that anti-HEV IgG may not be protective against HEV especially post transplant due to immunosuppression and clinical work up of transaminitis should include HEV RNA. Patients undergoing transplant should be advised against eating raw or undercooked meat
HEV virus is an important cause of hepatitis before and after transplantation.
The case showed a patient with HEV infection despite the prescene of high anti HEV antibodies.
Treatment of HEV infection with ribavirin is good option .
Anti HEV antiboies may not be protective of reinfection prior to transplantation.
Ultra-short reply, I wish you could write in more details for me to appreciate clarity of your thought process.
Introduction:
– Hepatitis E virus (HEV) infection is an important reason for acute hepatitis with increasing prevalence worldwide.
– HEV specific antibodies are developed after acute infection and thought to confer protection against re-infection.
– HEV gt3 can progress to a chronic infection with high morbidity and mortality in immunocompromised.
Case presentation:
– A 64-year-old man transplanted on April 2016 for FSGS and maintained on triple immunosuppression therapy.
– 2 months post-Tx, he had FSGS recurrence and treated with RTX, PLEX (26 times).
– 6 months post- Tx, he developed BKPyV viremia, treated with IS reduction and IVIG.
– November 2016, routine testing revealed elevated transaminases ( dropped after month) and GGT with normal US.
– March 2017, diagnosed with active HEV infection positive anti-HEV IgM & IgG.
– Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection
– Stored pre-transplant sample tested and it indicated resolved HEV infection before KT (positive anti-HEV IgG, negative IgM & HEV RNA).
– In September 2017, treated with ribavirin for 11 weeks , stopped for anemia.
– October 2017, HEV RNA negative and liver enzymes normalized indicated successful therapy.
Discussion:
-Chronic HEV infection can develop despite the presence of anti-HEV IgG.
-This indicates that HEV antibodies did not confer protection in this patient.
– The definitive protective antibodies titer has not been firmly assessed yet.
– HEV serological assays differ in their performance and standardization of antibody assays is under debate.
– Immunosuppressive therapy influence humoral immune response which affect antibodies titer, and caused impaired HEV-specific T-cell response
Conclusion:
-Anti-HEV IgG may not be protective, its value of testing is limited.
– Testing for HEV infection in patients with elevated liver enzymes.
– The diagnosis of HEV infection in immunosuppressed patients by NAT.
– Counseling for the risk of HEV infection if raw/ undercooked pig products is consumed.
– Further study is needed for the role of the humoral and T-cell immunity in HEV.
I like your summary.
Important clinical lessons:
1- The presence of anti-HEV IgG may not be protective thus limiting the value of testing
for anti- HEV IgG before the start of immunosuppressive regimens. no determined
definite cut off value for the protective HEV antibody level.
2- Clinical work-up upon increased liver enzymes should include testing for HEV
infection irrespective of the anti-HEV IgG status before immunosuppression.
3- Counseling patients at risk for chronic HEV infection regarding the consumption of
raw/ undercooked pig products seems advisable.
4- The role of the humoral and T-cell mediated immune response in cases of HEV
reinfection deserves further study.
. I like your summary, analysis and take home messages.
Summary
Hepatitis E virus (HEV) infection is now recognized as a major cause of acute hepatitis anf HEV antibodies are thought to provide protection.
This is a case report of patient who developed chronic HEV infection despite the presence of high level antibodies. This was treated with Ribavirin.
Five human pathogenic HEV genotypes are known
HEV genotype 3 is the dominant HEV genotype in Europe.
Presentation
HEV infection remains asymptomatic or presents as mild and self-limiting disease
Humoural response- anti-HEV IgM antibodies followed by the development of a robust antiHEV IgG response
No definitive minimum protective HEV antibody concentration has been established
Acute HEV gt3 infection can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality rates in immune compromised
Conclusions
· HEV testing should be done if liver enzymes are deranged.
· Anti HEV IgG may not be prtective thus limiting its testing before surgery
· Minimum protective antibody concentration of 2.5 World Health Organization (WHO) units/mL has been proposed
· Immunosuppressive therapies might also interfere with the HEV replication cycle
· HEV infection should be diagnosed using nucleic acid testing
· Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig is important
· The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
I appreciate that you mention genotypes with varied geographic distributions.
☆Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
__________________________________
◇ Background
▪︎Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
▪︎To date, five human pathogenic HEV genotypes are known.The dominant one in Europe is genotype 3 (gt3), which is transmitted zoonotically to humans.
▪︎HEV infection remains asymptomatic or presents as mild and self-limiting disease.
▪︎The humoral immune response begins with the rise of anti-HEV IgM Abs, followed by the development of a robust antiHEV IgG response.
▪︎The anti-HEV IgG antibody concentration then slowly declines over time but may remain detectable for years.
▪︎In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates. In these patients the HEV specific antibody response is variable or lacking at large.
_________________
◇ Case presentation:
▪︎The authors reported an immunocompromised patient who developed chronic HEV infection despite the presence of high level antibodies.
▪︎HEV infection was detected using RT-PCR upon diagnostic evaluation due to
increased liver enzymes.
▪︎Upon retrospective analysis of stored serum samples the authors have found that the patient was HEV RNA positive since 7 months. Chronic HEV infection was successfully treated with ribavirin.
◇ For clinical practice the following points remain important:
I. The presence of anti-HEV IgG may not be
protective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counsel patients at risk for chronic HEV infection.
V. The ability to identify patients with HEV reinfection who developed a chronic
course which was successfully treated with
ribavirin. The role of the humoral and T-cell
mediated immune response in cases of HEV
reinfection deserves further study.
◇ Conclusion
▪︎This case reported a patient who suffered from a chronic course of HEV infection, which was successfully treated with ribavirin.
▪︎ It underlines the importance of RT-PCR for HEV diagnostics in immunosuppressed
patients and supports the notion that HEV antibodies do not confer universal protection.
▪︎Counseling patients at risk for chronic HEV infection seems advisable.
▪︎The role of the humoral and T-cell mediated immune response in cases of HEV reinfection needs further study
I appreciate that you mention genotypes with varied geographic distributions.
Background
The zoonotic transmission of acute hepatitis caused by the hepatitis E virus (HEV) and its five genotypes through infected meat products, particularly genotype 3 in Europe, typically results in a mild, self-limiting sickness. IgM and IgG antibodies against HEV are part of the humoral immune response, and these antibodies may be detectable for years. Acute HEV gt3 infection can proceed to a chronic course in immunosuppressed patients, which can result in substantial morbidity and mortality. Despite having high levels of anti-HEV IgG antibodies, the case study reveals the development of chronic HEV infection.
Case presentation
A 64-year-old man with focal segmental glomerulosclerosis (FSGS) on tacrolimus-based triple drug immunosuppression, a history of treatment for FSGS recurrence (plasmapheresis and rituximab), and BK viremia experienced elevated liver enzymes (AST, ALT, and GGT) in November 2016 despite the absence of any clinical symptoms. Despite AST and ALT returning to normal in March 2017, GGT remained high. On inquiry, HEV RNA PCR, anti-HEV IgM, and anti-HEV IgG were positive. HEV genotype 3c was the type. Retrospective blood sample analysis found positive HEV RNA in a sample taken in September 2016 and positive anti-HEV IgG with negative anti-HEV IgM and HEV RNA in a sample taken before the transplant. Anti-HEV IgM levels increased concurrently with a sharp rise in anti-HEV IgG up until February 2017. In September 2017, the patient underwent an 11-week course of ribavirin treatment before the treatment was stopped due to anemia. In October 2017, liver enzymes returned to normal and plasma HEV RNA became negative.
Discussion
The instance described demonstrates that anti-HEV antibodies do not provide protection against HEV reinfection. A minimal protective threshold of 2.5 WHO units/mL for anti-HIV antibodies has been proposed. Anti-HEV IgG titres below 6 IU/mL (or 7 WHO units/mL) have been proven to not protect against HEV reinfection. Anti-HEV antibodies in the index patient were 7 IU/ml and were therefore not protective. The use of rituximab resulted in B cell reduction, which ultimately led to reinfection despite the presence of anti-HEV antibodies. Anti-HEV antibodies decreased post-transplant (due to immunosuppressive drugs), compromising the ability to prevent HEV reinfection. It has been demonstrated that tacrolimus increases HEV infection of hepatic cells, whereas MMF suppresses HEV proliferation. Poor T cell response to HEV also plays a role in HEV reinfection.
In conclusion, this report illustrates that anti-HEV IgG may not be protective, elevated liver enzymes would call for HEV infection testing, immunosuppressed patients should undergo HEV NAT testing, patient dietary counseling regarding consumption of raw or undercooked meat (pig) is crucial, and HEV reinfection can be successfully treated with ribavirin.
I appreciate your understanding about the need to modify immunosuppression when infected with Hep E, well-supported by level of recommendation.
IV. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
Summarize this article.
Hepatitis E virus (HEV) infection
Transmission:
Presentation:
Clinical practice points:
I appreciate your strategy in relation to Hep E infection and transplant.
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report.
Background.
HEV is considered one of the most common cause of acute hepatitis, especially HEV genotype 3 (gt3) is the dominant HEV genotype and after infection HEV IgG rising but slowly declines over time, and reported re-infection of HEV in some immunocompromised cases despite the presence of detectable anti-HEV IgG before.
This article present a post kidney transplant case complicated with HEV re-infection and its response to Ribavirin, that highlight the role of immunosuppression on humoral and T-cell mediated immune response.
Added some clinical advices such as:
=Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
=In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
=Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
Conclusion:
The possibility of HEV re-infection is still standing despite the presence of detectable anti-HEV IgG before and there is no a definitive protective titer has not been firmly assessed yet in immunocompromised patients and should be treated by Ribavirin.
I appreciate your strategy in relation to Hep E infection and transplant.
Summary
Background
HEV recognised as a major cause of hepatitis worldwide.
There are 5 genotypes, genotype 3 dominant in Europe and transmitted though consumption of contaminated meat.
General population causes a mild self limiting disease, however in immunosuppressed infection may progress to chronic infection.
The case
64 year old with FSGS transplanted in 2016 and initiated on triple maintenance immunosuppressive therapy.
Post transplant complications:
Discussion.
HEV antibodies are pivot to control infection, however a titer that confers protection has not been defined.
Impaired B cells in this patient who had received rituximab may have contributed to reinfection despite the fact that the patient had HEV antibodies.
IgG anti-HEV titers decreased shortly after transplant due to the immunosuppressive therapy.
Ribavarin is the only current treatment available for HEV.
Pegylated interferon has some activity against HEV however can’t be used in SOT due to risk of rejection.
Conclusion
IgG anti-HEV may not be protective.
Elevated liver enzymes warrants testing for HEV infection irrespective of anti-HEV status prior to transplant.
HEV infection in transplant recipient should be diagnosed with nucleic acid amplification test.
Patients should be counselled on the infection from consumption of raw/undercooked infected meat.
Role of humoral and T cell mediated immune response in HEV infection requires further study.
I appreciate that you mention genotypes with varied geographic distributions.
Background: Hepatitis E Virus (HEV) with its 5 genotypes is responsible for acute hepatitis worldwide (especially genotype 3, gt3 in Europe) through zoonotic transmission via contaminated meat products culminating in mild, self-limiting disease usually. Humoral immune response includes IgM antibodies followed by IgG antibodies against HEV which may remain detectable for years. In immunosuppressed patients, acute HEV gt3 infection can progress to chronic course leading to high morbidity and mortality. The case presented shows development of chronic HEV infection despite presence of high anti-HEV IgG antibodies.
Case Presentation: A 64-year-old renal transplant recipient (April 2016), with basic disease of focal segmental glomerulosclerosis (FSGS), on tacrolimus based triple drug immunosuppression, and history of treatment for FSGS recurrence (Plasmapheresis and rituximab) as well as BK viremia developed elevated liver enzymes (AST, ALT, GGT) in November 2016 in absence of any clinical symptoms. GGT was still elevated in March 2017, although AST and ALT normalized. On investigation, HEV RNA PCR, anti-HEV IgM and anti-HEV IgG were positive. The genotype was HEV genotype 3c. Retrospective analysis of stored blood samples revealed positive HEV RNA in September 2016 sample and positive anti-HEV IgG with negative anti-HEV IgM and HEV RNA in the pre-transplant blood sample. The anti-HEV IgG rapidly rose upto February 2017, and then fell, with concomitant rise in anti-HEV IgM. Patient was treated with ribavirin in September 2017 for 11 weeks, with cessation of therapy due to anemia. Plasma HEV RNA became negative in October 2017 and liver enzymes became normalized.
Discussion: The presented case illustrates the fact that anti-HEV antibodies do not confer protection from HEV reinfection. A value of 2.5 WHO unit/ml anti-HEV antibodies has been proposed as the minimum protective value. It has been shown that anti-HEV IgG titres less than 6 IU/ml (or <7 WHO unit/ml) do not protect against HEV reinfection. The index patient’s anti-HEV antibodies were <7 IU/ml, and were hence non-protective. The use rituximab led to B cell depletion, causing loss of functional B cell ultimately leading to reinfection despite anti-HEV antibodies. Anti-HEV antibodies reduced post-transplant (due to immunosuppressive medications), affecting the ability to counter HEV re-infection. Tacrolimus has been shown to increase HEV infection of hepatic cells while MMF inhibits HEV proliferation. Impaired HEV specific T cell response also has role in HEV reinfection.
Conclusion: The case highlights that anti-HEV IgG may not be protective, elevated liver enzymes would warrant HEV infection testing, HEV NAT testing should be done I immunosuppressed patients, patient dietary counselling regarding raw/undercooked meat (pig) consumption is very important, and HEV reinfection can be treated successfully with ribavirin.
I appreciate that you mention genotypes with varied geographic distributions.
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
Summary:
· Although HEV is a major cause of acute hepatitis worldwide with acquired lifelong protection, it was reported to have a chronic course of HEV infection.
· The case had KT due to ESKD 2ry to FSGS and was maintained on tac based triple IS therapy.
· Testing for HEV RNA was requested due to elevated liver enzymes.
· Diagnosis of chronic infection was made as PCR was positive in stored sample withdrawn 7 months before this time.
· Ribavirin was used for treatment.
· RT-PCR is the standard for diagnosis in immunosuppressed patients.
· There is a notion that HEV antibodies do not confer universal protection, as this case has positive PCR in spite of positive antibodies in the serum.
· Counseling patients about risk of chronic HEV infection is advisable and better avoidance of undercooked pork meat.
· The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study
. I like your summary.
Thanks dear professor
April 2016
A 64-year-old man
FSGS underwent RTX
TAC- MMF- PRED.
June 2016
rituximab and PE (26 times) with albumin and fresh frozen plasma (recurrence of FSGS), resolved until October 2016.
BKV viremia three months after transplantation.
Prednisone was tapered and MMF was reduced. BKV viremia remained below 1000 copies/mL plasma from October 2016 onwards and mycophenolate mofetil was increased.
IVIG were given once at the end of June 2016 due to hypogammaglobulinemia.
November 2016,
elevated AST , ALT and γ-GT .
March 2017,
1- increased γ-GT but AST and ALT normal
US was normal.
2- Testing for hepatitis C virus RNA was negative
3- HEV RNA was detected using RT PCR indicating active HEV infection.
4- anti-HEV IgM and IgG using ELISA were positive.
Retrospective analysis of stored plasma samples showed ;
1- stored plasma samples taken before kidney transplantation
anti-HEV IgG positive
anti-HEV IgM negative
HEV RNA resolved HEV infection before transplantation
2- in September 2016
Anti-HEV IgG : a rapid rise
HEV RNA : first detectable
anti-HEV IgM : negative
3- in February 2017
anti-HEV IgM became positive
detection of anti-HEV IgG antibodies directed against the C terminal end of the ORF2 protein (O2CGt1 and O2CGt3) whereas antibodies against the middle and the N-terminal end of ORF2 were not detectable
4- In September 2017,
treatment with ribavirin was initiated.
He received an 11week course of ribavirin (off-label use) and therapy was stopped due to anemia.
5 – in October 2017
HEV RNA in plasma: was first negative and remained negative indicating successful therapy.
Liver enzymes returned back to normal range.
Discussion and conclusions
1- It is a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation.
Reinfection indicates that HEV antibodies did not confer protection in this patient.
2- HEV antibodies have been standardized concentration of 2.5 (WHO) units/mL.
However, a definitive protective titer has not been firmly assessed yet.
Choi and coworkers demonstrated that low HEV-IgG titers (<6IU/ml) were not protected against HE reinfection
French study found that a low anti HEVIgG of<7 WHO units/mL did not protect against reinfection
In this patient , despite the rapid anti-HEV IgG response this did not lead to clearance of HEV RNA from the blood in our patient.
This supports the notion of a limited protective humoral immune response.
Wang and colleagues showed that tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect at all
3- the rituximab induced B cell depletion might have influenced the development of reinfection despite the presence of HEV antibodies.
4- the T-cell mediated immune response remains largely unclear in HEV infection and deserves further study.
Treatment
1- ribavirin was successful in this patient but anemia as well-known side effect
2- Currently, ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently needed.
3- Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
For clinical practice the following points remain important:
I. The presence of anti-HEV IgG may not be protective
II- Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV. Counseling patients at risk for chronic HEV infection seems advisable.
In conclusion,
1- we were able to identify a patient with HEV reinfection who developed a chronic course which was successfully treated with ribavirin.
2- The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
I make note of your interpretation of serological and molecular testing reports pertaining to Hep E infections in relation to timings in the natural history. I like your summary.
Background
Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
There are 5 HEV genotypes , HEV genotype 3 (gt3) is the common and dominant in Europe.it transmitted from animal to human .
HEV generally a symptomatic or presenting as mild disease and self- limiting disease.
The humoral immune response begins with the rise of anti-HEV IgM antibodies followed by the development of antiHEV IgG response .
The anti-HEV IgG antibody concentration then slowly declines over time but may remain detectable for years.
Acute HEV gt3 infection In immunosuppressed patients can progress to a chronic course which increase morbidity and mortality rates.
Case presentation
A 64-year-old man with a history of focal segmental glomerulosclerosis underwent kidney transplantation in April 2016. Immunosuppressive medication was tacrolimus ,MMF and prednisone. he received rituximab 750 mg twice and plasma exchange (26 times) with albumin and fresh frozen plasma.
Three month post transplantation affected by BKV viremia and hypogammaglobulinemia,Immune suppressions was reduced till infection released then initial dose stated again .
Seven month post transplantation discover during routine he had high ALT and γ-GT with normal liver US ,4 month after γ-GT still high but AST and ALT were normal .
Investigations was
1. HCV RNA was negative
2. HEV by PCR was positive.
3. anti-HEV IgM and IgG by ELISA were positive.
4. HEV RNA over the last 7months was detected (from stored plasma).
5. anti-HEV IgG positive and anti-HEV IgM negative (from stored plasma).
After six month, treatment started with ribavirin 200 mg in five dose daily ,his liver enzymes still high (AST (77U/ L), ALT (78U/L), and γ-GT (226U/L)
Ribavirin continue for 11 weeks but stopped due to anemia .
HEV RNA become negative and liver enzyme return to normal .
Discussion
conclusion,
we were able to identify a patient with HEV reinfection who developed a chronic course which was successfully treated with ribavirin.
The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
I like your well structured detailed summary.
I appreciate your strategy in relation to Hep E infection and transplant.I appreciate that you mention genotypes with varied geographic distribution.
Conclusion
I like your well structured detailed summary.
I appreciate your strategy in relation to Hep E infection and transplant.I appreciate that you mention genotypes with varied geographic distribution.
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
Background
· Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide
· HEV infections are linked to the consumption of HEV contaminated meat products.
· Although HEV specific antibodies are thought to confer protection against re-infection, this still need to be proved.
· In immunosuppressed patients, however, acute HEV infection can progress to a chronic course with high morbidity and mortality rates.
Case presentation
· A 64-year-old man with a history of FSGS underwent kidney transplantation.
· Immunosuppressive medication after transplantation included tacrolimus, mycophenolate mofetil and prednisone.
· Recurrence of FSGS occurred 2 months post transplantation for which he received rituximab and therapeutic plasma exchange.
· His post-transplantation course showed BKV viremia three months after transplantation, IS treatment was reduced for some time till viremia was controlled.
· 7 moths post transplantation, routine laboratory testing revealed elevated AST, ALT, and γ-GT. 4months later, he was clinically well but still, laboratory tests showed an increased γ-GT with 215IU/ L, but AST (44U/L) and ALT (45U/L) returned back to normal range. Abdominal ultrasound did not reveal hepatic lesions or signs of liver cirrhosis. Testing for hepatitis C virus RNA was negative, however, HEV RNA was detected using RT-PCR.
· Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7months beginning at 5 months post transplantation consistent with chronic HEV infection.
· Phylogenetic analysis of HEV RNA demonstrated an HEV genotype 3c.
· Stored plasma samples taken before kidney transplantation were positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before transplantation.
· Anti-HEV IgG showed a rapid rise after HEV RNA was first detectable.
· Anti-HEV IgM remained negative and it became positive, 4 months after detection of HEV RNA.
· To better appreciate the level of HEV IgG antibodies they used a quantitative HEV. Interestingly, it showed that the early samples tested (shortly after transplantation) HEV IgG were borderline and negative at 4 months. Subsequently, a rise in HEV IgG occurred at 10 month post -transplant.
· Later on treatment with ribavirin (200mg, 5 doses daily) was given for 11 weeks.
· HEV RNA in plasma was first negative one month after initiation of therapy and remained negative.
Discussion
· This case showed chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation.
· This suggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient.
· A definitive protective titer of anti-HEV IgG has not been firmly assessed yet.
· They used another quantitative assay which was calibrated against the WHO standard and it showed that anti-HEV IgG was below 7 IU/ ml supporting the hypothesis of non-protective antibody titers in our patient.
· Despite the rapid anti-HEV IgG response, this did not lead to clearance of HEV RNA from the blood in this case. This further supports the notion of a limited protective humoral immune response.
· Rituximab leading to impaired B cells in this immunosuppressed patient might have contributed to reinfection despite the presence of HEV antibodies.
· The T-cell mediated immune response remains largely unclear in HEV infection and deserves further study.
· They did not detect HEV RNA before and shortly after transplantation arguing against reactivation in our patient.
· Treatment with ribavirin was successful in this patient, in spite of discontinuation of antiviral therapy after 11 months treatment due to anemia.
Conclusions
· Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
· In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing
I appreciate your strategy in relation to Hep E infection and transplant.
Hepatitis E virus (HEV) infection is increasingly recognized worldwide as a major cause of acute hepatitis.
Presentation of case
was an immunocompromised patient who developed chronic HEV infection despitehe presence of high antibody levels. HEV infection was detected by RTPCR after
diagnostic evaluation due to elevated liver enzymes. Retrospective analysis of stored serum samples revealed that this patient had been positive for HEV RNA for 7 months. Ribavirin successfully treated chronic HEV infection
Essentials of Clinical Practice:
The presence of antiHEV IgG may not be protective, which limits the value of testing for anti-HEV IgG before starting immunosuppressive therapy.
Clinical workup after elevated liver enzymes should include testing for HEV infection, regardless of anti-HEV IgG status prior to immunosuppression
In immunocompromised patients, nucleic acid testing should be used to diagnose HEV
infection.Four.Consumption of raw/undercooked pork products appears to be recommended for patients at risk of chronic HEV infection.
In conclusion, we are able to identify a patient reinfected with HEV who develop a chronic course and was successfully treated with ribavirin.
The role of humoral and T cell-mediated immune responses in cases of HEV
re infection deserves further study.
I appreciate your strategy in relation to Hep E infection and transplant.
Chronic HE infection after kidney transplantation with an antibody response suggestive of Reinfection
Summary of the Article
Background
Discussion
Conclusion
I like your well structured detailed summary in relation to each advice in relation to the type of disease and corresponding treatment. I appreciate your strategy in relation to Hep E infection and transplant.
Background
There are 5 HEV genotypes , genotype 3 is the most dominant in Europe .
Genotype 3 is transmitted zoonotically to humans through consumption of undercooked meat.
Usually it is asymptomatic and self limited.
Humoral immunity starts with Ig M rise then IgG which decreases but can persist for years meanwhile it’s protective role is controversial.
Genotype 3 can progress to a chronic course in immunocompromised cases.
This is a case report of a renal transplant recipient whom developed Chronic HEV infection shortly after transplantation .
Case report
A 64-year-old male received kidney transplantation due FSGS in
April 2016.
Immunosuppressives for maintenance were ,tacrolimus, MMF and prednisone.
Also rituximab 750mg twice 3 months later and 26 times of plasma exchange for FSGS recurrence that was cured on October.
He had BK viremia 3 months after transplantation.
Prednisolone was tapered to 10 mg /day and MMF was reduced to 250 mg bid ,BK viremia level decreased less than 1000 copies /ml and MMF dose was doubled.
IVIG was given once in June 2016due to hypogammaglobulinemia.
5months later he had mild elevation of his liver enzymes and high gammaGT on routine testing with unremarkable hepatic imaging.
November 2017, his liver enzymes returned to normal but gamma GT was still elevated and unremarkable hepatic US findings ,he was on Tac 1 mg bid ,MMF 500 mg bid and prednisolone 7.5 mg OD.
HEV RNA was positive using RT-PCR, anti-HEV IgM and anti HEVIgG were positive by ELISA test.
Retrospective testing of stored plasma 7 months ago showed positive HEV denoting chronic HEV infection, positive for anti-HEV IgG and negative for anti-HEV IgM indicating cure before transplantation.
September 2016 ,Ig G level rose when HEV RNA was noticed and Ig M levels were negative then turned positive Feb 2017
It was analysed as HEV genotype 3.
September 2016 he started ribavirin for 11 weeks but was stopped due to anemia.
HEV RNA was negative in October 2017 and continued negative denoting cure . Liver enzymes were normalised .
Infection source was not discovered.
Discussion
A case of chronic HEV infection with reinfection in a renal transplant recipient.
There is no specific protective titer for HEV Ab
A french study on immunocompromised patients demonstrated that a low anti-HEV IgG of < 7 WHO units/mL wont be protective against reinfection.
The current case experienced a rapid rise in anti-HEV IgG then an anti-HEV IgM response shortly afterwards but this immune response was not enough to clear the viral infection.
Rituximab could have affected HEV Ab production as in Immunocompromisation with impaired B cell might have lead to HEV reinfection.
In a study antibodies against the C-terminal end of ORF2 which have been regularly detected indicates the immune response of blood donors.
HEV IgG level decreased after immunosuppressive therapy indicating it’s influence on humoral response .
Immunosuppression affects HEV replication cycle.
Previous studies published that tac can enhance HEV infection, MMF inhibits it’s replication and steroids had no effect.
Chronic HEV infection impairs HEV specific T cell response.
In the current case with chronic HEV infection ,HEV-specific CD8+ Tcell response was diminished compared to acute disease , but was partially restored with ribavirin .
In fact ribavirin cleared the virus but anemia occurrence obliged them to stop it .
Peg INF can lead to rejection.
Regarding Sofosbuvir, further studies are needed.
Conclusion
–Analysis of HEV Ig G before immunosuppression is of limited importance as it is not protective.
-Elevation of liver enzymes necessitate testing for HEV infcetion regardless of HEV Ig G level before immunosuppression.
-HEV Nucleic acid testing is the method of diagnosis
in immunosuppressed cases
-Avoidance of undercooked meat need to be educated for cases at HEV infection risk.
– Further study is needed for humoral and T-cell mediated immune response in HEV reinfection.
I like your well structured detailed summary in relation to each advice in relation to the type of disease and corresponding treatment. I appreciate your strategy in relation to Hep E infection and transplant.
Case report; Summary
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
The recipient:
· A 64-year-old man, underwent KT after ESRD/FSGS on April 2016.
· Immunosuppressive medication included tacrolimus, mycophenolate mofetil and prednisone.
· He received rituximab 750 mg twice and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as replacement fluid due to recurrence of FSGS, which subsequently resolved until October 2016.
· His post-transplantation course showed BKV viremia three months after transplantation and received IVIG once at the end of June 2016 due to hypogammaglobulinemia.
· November 2016, routine laboratory testing revealed elevated liver enzymes (AST,ALT & γ-GT) and liver ultrasound showed no pathological findings.
· March 2017, he was clinically well and his physical examination was without pathological findings. Still, laboratory tests showed an increased γ-GT but AST and ALT returned back to normal range. Abdominal ultrasound did not reveal hepatic lesions or signs of liver cirrhosis.
· Testing for hepatitis C virus RNA was negative.
· HEV RNA was detected using RT-PCR indicating active HEV infection. Concomitantly anti-HEV IgM and IgG using ELISA were positive.
· A fragment of open reading frame (ORF) demonstrated an HEV geno- type 3c.
· Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection.
· Stored plasma samples taken before kidney transplantation were positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before transplantation.
· In September 2017, treatment with ribavirin (200 mg, 5 doses daily) was initiated. He received an 11- week course of ribavirin (off-label use) and therapy was stopped due to anemia.
· October 2017, HEV RNA remained negative indicating successful therapy. Liver enzymes returned back to normal range.
Discussion:
1. The mode of acquisition of HEV infection in this patient remains unclear but could be related to HEV- contaminated blood products, an HEV-contaminated transplant organ, or food uptake after transplantation.
2. Despite the presence of detectable anti-HEV IgG before and after kidney transplantation, HEV reinfection indicates that HEV antibodies did not confer protection in this patient.
3. Impaired B cells in this immunosuppressed patient might have contributed to reinfection despite the presence of HEV antibodies.
4. Reduction of anti-HEV IgG titers, shortly after transplantation, suggests an influence of the immuno- suppressive therapy on the humoral immune response.
5. Wang and colleagues showed that: tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect at all.
6. The T-cell mediated immune response remains largely unclear in HEV infection.
7. In this case repot, it was shown that the HEV-specific CD8+ T- cell response in chronic HEV patients was diminished in comparison to the acute disease course, but was partially restored after ribavirin therapy.
8. Although associated with anaemia, ribavirin is the only drug available for treatment of HEV infection.
9. Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
10.In vitro data showed that the drug sofosbuvir, known as a polymerase inhibitor of hepatitis C virus, may also be effective but beyond case reports no data is available to date.
Conclusion:
1. This case underlines the importance of RT-PCR for HEV diagnostics in immunosuppressed patients and supports the notion that HEV antibodies do not confer universal protection.
2. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
3. Counseling patients at risk for chronic HEV infection seems advisable.
I appreciate your clinical approach to patient with Hep E infection in background of immunosuppression. I like your well structured detailed summary.
kidney transplantation with an antibody response suggestive of reinfection: a case report
Introduction:
Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
The anti-HEV IgG antibody concentration slowly declines over time but may remain detectable for years.
HEV infection remains asymptomatic or presents as mild and self-limiting disease, HEV IgM detected early in disease and declines over time, HEV IgG may be detectable for years.
Five genotypes are known (genotype 3 is the dominant one in Europe), Seroprevalence rates range from <1%-52% across Europe.
In immunosuppressed patients, however, acute HEV Genotype 3 infection can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality rate.
HEV specific antibodies that confer protection against re-infection is controversial.
The Study Demonstrate the importance of RT-PCR for diagnosing HEV in order to treat the patient early and prevent bad outcome post-transplant.
Aim of the study:
A case report of an immunocompromised patient who developed chronic HEV infection despite the presence of high-level antibodies (high anti-HEV IgG pre- and post-transplantation)
Case presentation:
A 64-year-old male with ESRD 2/2 FSGS, Post kidney transplantation, and maintained on tacrolimus, mycophenolate, and prednisolone.
Patient received rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as replacement due to recurrence of focal segmental glomerulosclerosis, which subsequently resolved until October 2016.
History of BK viremia treated by reduction of immunosuppressive medications (MMF), and Intravenous immunoglobulins (10 g) were given once at the end of June 2016 due to hypogammaglobulinemia.
In November 2016, found to have modest elevation of liver function ALT 81, AST and gamma GT 276.
HEV RNA was detected using RT-PCR indicating active HEV infection. Concomitantly anti-HEV IgM and IgG using ELISA were positive.
Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection.
Discussion:
Immunosuppressive therapy affects the humoral immune response and interferes with the HEV replication cycle leading to low anti-HEV IgG titers.
Chronic HEV infection is associated with an impaired HEV-specific T-cell response in transplant patients
The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti-HEV IgG before the start of immunosuppressive regimens.
Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
Tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect.
Ribavirin is the only drug available for treatment of HEV infection. Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
Sofosbuvir (a polymerase inhibitor of hepatitis C virus), may also be effective.
The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti-HEV IgG before the start of immunosuppressive regimens.
Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression
In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing
Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
Conclusions:
HEV reinfection with a chronic course is successfully treated with Ribavirin.
Ribavirin is the drug of choice for treatment of HEV and anemia the common side effect of ribavirin.
HEV antibodies may not confer universal protection against HEV
In immunosuppressed patients, RT-PCR for HEV diagnosis is important.
Serum samples before transplantation should be kept for testing HEV RNA when needed.
Counseling of patients at risk for chronic HEV infection is advisable,
The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
I like your well structured detailed summary.
I appreciate your clinical approach to patient with Hep E infection in background of immunosuppression.
Background
Hepatitis E virus (HEV ) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
The anti-HEV IgG antibody concentration slowly declines over time but may remain detectable for years.
HEV specific antibodies are thought to confer protection against re-infection this topic remains controversial to date.
Acute HEV gt infection can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality rates.
In these patients the HEV specific antibody response is variable or lacking at large.
We report a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG preand post-transplantation and we describe and characterize the HEV-specific antibody response over time
Case presentation
A 64-year-old man with a history of focal segmental glomerulosclerosis underwent kidney transplantation in.
Immunosuppressive medication after transplantation included tacrolimus, mycophenolate mofetil and prednisone.
He received rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as.
The Creative Commons Public Domain Dedication waiver applies to the data made available in this article, unless otherwise stated
In March 2017, he had a routine follow-up visit at the transplant center and his medication included tacrolimus (1 mg twice daily, trough level 5–8 ng/mL), mycophenolate mofetil (500 mg twice daily), and prednisone (7.5 mg once daily)
He was clinically well and his physical examination was without pathological findings.
Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection .
Anti-HEV IgG showed a rapid rise after HEV RNA was first detectable in September 2016 whereas anti-HEV IgM remained negative.
Due to the retrospective nature of the HEV diagnosis no information on food consumption was possible
Findings
Recent data demonstrated HEV seroprevalence rates ranging from < 1% up to 52% across Europe.
Discussion and conclusions
We were able to show a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation
This suggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient.
In immunocompromised patients a French study found that a low anti-HEV IgG of < 7 WHO units/mL did not protect against reinfection.
We used another quantitative assay which was calibrated against the WHO standard.
The epitope-specific analysis of the immune response showed antibodies directed against the C-terminal end of ORF2 which have been regularly detected in another study analyzing the immune response of blood donors.
In our patient this was paralleled by an increase of anti-HEV IgG.
Anti-HEV IgG titers decreased shortly after transplantation suggestion an influence of the immunosuppressive therapy on the humoral immune response
The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study
I appreciate your clinical approach to patient with Hep E infection in background of immunosuppression. I like your well structured detailed summary.
Summarise this article
Introduction
v HEV infection is a major cause of acute hepatitis worldwide
v Five genotypes are known (genotype 3 is the dominant one in Europe)
v Seroprevalence rates range from <1%-52% across Europe
v HEV specific antibodies that confer protection against re-infection is controversial
v Aim of the study: a case report of an immunocompromised patient who developed chronic HEV infection despite the presence of high level antibodies (high anti-HEV IgG pre- and post-transplantation)
Case presentation
A 64-year-old man underwent kidney transplantation in April 2016 (cause was FSGS). Immunosuppressive were tacrolimus, MMF and prednisone. Patient received rituximab 2 months after transplant and therapeutic plasma exchange with albumin and FFP as replacement fluid due to recurrence of FSGS. He developed BKV viremia and hypogammaglobulinemia three months after transplantation
Seven months after transplant, routine laboratory testing revealed elevated AST (62U/L), ALT (81U/L), and γ-GT (276U/L. Ultrasound of the liver was normal. Four months later, γ-GT is still high (215IU/ L) but AST and ALT returned back to normal range and HEV RNA was detected using RT-PCR. Anti-HEV IgM and IgG using ELISA were positive. Retrospective analysis of stored serum samples revealed that the patient was HEV RNA positive since 7months. In September 2017, treatment with ribavirin (200mg, 5 doses daily) was started (11week) with successful therapy
Discussion
o Immunosuppressive therapy affects the humoral immune response and interferes with the HEV replication cycle leading to low anti-HEV IgG titers
o Chronic HEV infection is associated with an impaired HEV-specific T-cell response in transplant patients
o Treatment with ribavirin was successful in our patient but anemia as well-known side effect of ribavirin led to the discontinuation of antiviral therapy
o Currently, ribavirin is the only drug available for treatment of HEV infection
o Pegylated interferon-alfa has antiviral activity against HEV, but has a high risk of rejection (not used)
o Sofosbuvir (a polymerase inhibitor of hepatitis C virus), may also be effective
For clinical practice:
1. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressive regimens
2. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression
3. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing
4. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable
Conclusions
o HEV antibodies may not confer universal protection against HEV
o In immunosuppressed patients, RT-PCR for HEV diagnosis is important
o Counseling of patients at risk for chronic HEV infection is advisable
o The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study
I appreciate your clinical approach to patient with Hep E infection in background of transplant.
Summary
Introduction
This article is about the importance of RT-PCR for diagnosing HEV in order to treat the patient early and prevent bad outcome post transplant. The study itself is based on a recipient who had a recurrence of Hepatitis E infection despite having high levels of antibodies.
Discussion
Chronic HEV infection is possible even if the patient has high levels of detectable anti HEV IgG antibodies before and after transplant. This means that HEV antibodies do not provide unconditional protection to the patient. According to WHO, a minimum antibody concentration of 2.5 units/mL can confer protection to the patient, although this is not without its limits. The patient can still develop chronic course of infection of hepatitis E.
Booster shots can lead to a rapid rise in anti HEV IgG followed by a rise in anti HEV IgM response. However, this may not lead to complete clearance of HEV RNA from the blood of the patient. This adds to the basic notion of limited protective humoral immune response that might allow space for reinfection, especially in immmunocompromised patients such as transplant recipients.
Since functional B cells are one of the mainline participants in controlling infection in the human body, impaired B cell function can contribute to risk of reinfection despite the presence of HEV antibodies in the immunocompromised patient.
Immunosuppressive agents also play a role in contributing to reinfection in the transplant recipient. Drugs such as tacrolimus have been documented to promote infection of liver cells with HEV whereas MMF inihibited HEV replication. Steroids remained neutral and did not appear to play a role at all in reinfection.
Thus, it is possible for the clinical course of HEV to be impacted by immunosuppressive regimen of the recipient, further underlining the importance of careful monitoring of immune response and serology of the patient upon administration of each of these immunosuppressive drugs, especially in the first year of transplantation.
Conclusion
Given all the data that we have seen with respect to HEV reinfection of transplant recipients, and the consensus that we have formed about the agents that can contribute to this risk, it is essential to note that HEV reactivation is not a common occurrence, but is actually rare.
Early detection through the usage of RT-PCR is paramount to managing the infection effectively, with ribavirin forming the frontline method of treatment. Anemia is a common side effect of this drug, and thus monitoring Hb levels, as well as making provisions for blood transfusions is essential for smooth application and completion of antiviral therapy.
PEG interferon has been described as an alternative treatment in cases which as resistant to ribavirin, but this cannot be used in patients with stem cell transplant or SOT with high risk of rejection.
Polymerase inhibitor of hepatitis C virus, Sofosbuvir, may be effective but this warrants further evidence before applying into proper clinical practice.
When increased liver enzymes are detected, it is important to do a clinical working for testing HEV infection irrespective of anti HEV IgG status before immunosuppression commenced. Nucleic acid testing is to be done.
Patient counseling regarding the bad effects of undercooking meat is an important measure to be taken for preventing or reducing the incidence of HEV infection in immunocompromised hosts.
I appreciate your clinical approach to patient with Hep E infection in background of transplant.
Summarise this article
Introduction:
Case presentation:
A 64-year-old male with ESRD secondary to FSGS, underwent a kidney transplantation, and maintained on tacrolimus, mycophenolate, and prednisolone.
The Pt. received rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as replacement fluid due to recurrence of focal segmental glomerulosclerosis, which subsequently resolved until October 2016.
H/O BK viremia treated by reduction of immunosuppressive medications (MMF), and Intravenous immunoglobulins (10 g) were given once at the end of June 2016 due to hypogammaglobulinemia.
In November 2016, found to have modest elevation of liver function ALT 81, AST and gamma GT 276.
HEV RNA was detected using RT-PCR indicating active HEV infection. Concomitantly anti-HEV IgM and IgG using ELISA were positive. Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months beginning in September 2016 consistent with chronic HEV infection.
Discussion:
1. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti-HEV IgG before the start of immunosuppressive regimens.
2. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
3. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
4. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
5. tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect.
6. Ribavirin is the only drug available for treatment of HEV infection. Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
Conclusion:
HEV reinfection with a chronic course is successfully treated with Ribavirin.
Serum samples before transplantation should be kept for testing HEV RNA when needed.
The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
I appreciate your strategy in relation to Hep E infection and transplant.
AIM OF Article
I. The presence of anti-HEV IgG may not be protective thus limiting the value of testing for antiHEV IgG before the start of immunosuppressive regimens.
II. Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III. In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing
. IV. Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
V. identify a patient with HEV reinfection who developed a chronic course which was successfully treated with ribavirin.
Case presentation
A 64Y man with a history of FSGS underwent kidney transplantation2016
On tacrolimus, mycophenolate mofetil and prednisone.
Had recurrence of FSGS received rituximab -therapeutic plasma exchange
Had BKV INFECTION 3 MONTH AFTER TRANSPLANT AND TREATED
Had evealed elevated AST – ALT , and γ-GT
Abdominal ultrasound did not reveal hepatic lesions or signs of liver cirrhosis.
Testing for hepatitis C virus RNA was negative,
HEV RNA was detected using RT-PCR indicating active HEV infection. Concomitantly anti-HEV IgM (71.5 AU/mL) and IgG (149 AU/mL) using ELISA were positive.
To better appreciate the level of HEV IgG antibodies we used a quantitiative HEV ELISA (Anti-HEV ELISA, Euroimmun), which was calibrated against the WHO standard and expresses HEV IgG in IU/ml. Interestingly, we were able to show that the early samples tested HEV IgG borderline (April 2016) and negative (August 2016), respectively
He received an 11- week course of ribavirin and therapy was stopped due to anemia. HEV RNA in plasma was first negative in October 2017 and remained negative indicating successful therapy.
Liver enzymes returned back to normal range.
The mode of acquisition of HEV infection in this patient remains unclear but could be related to HEV contaminated blood products, an HEV-contaminated transplant organ, or food uptake after transplantation
Upon review of the clinical charts we could exclude the administration of blood transfusions shortly before transplantation.
The patient had no recent travel. Due to the retrospective nature of the HEV diagnosis no information on food consumption was possible.
Discussion and conclusions
a case of chronic HEV infection despite the presence of detectable anti-HEV IgG before and after kidney transplantation. This suggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient.
HEV antibodies are considered to be pivotal to control the infection.
Recently, HEV antibodies have been standardized and a minimum protective antibody concentration of 2.5 World Health Organization (WHO) units/mL has been proposed . However, a definitive protective titer has not been firmly assessed yet.
Choi and coworkers recently demonstrated that rhesus macaques with low HEV-IgG titers (< 6 IU/ml) were not protected against HEV reinfection
in immunocompromised patients a French study
found that a low anti-HEV IgG of < 7 WHO units/mL did not protect against reinfection
Interestingly two issue in our case
1-our patient showed a rapid rise in anti-HEV IgG which was followed by an anti-HEV IgM response shortly after. This pattern is typical for a booster immune response and has been demonstrated for HEV in vivo . However, despite the rapid anti-HEV IgG response this did not lead to clearance of HEV RNA from the blood in our patient. This further supports the notion of a limited protective humoral immune response.
2-the rituximab induced B cell depletion might have influenced the development of HEV antibodies in our patient but anti-HEV IgG levels did never fall below the cut-off of the assay. It has been shown that functional B cells are instrumental to control the infection and that antibodies might not be the only correlate of protection Thus, impaired B cells in our immunosuppressed patient might have contributed to reinfection despite the presence of HEV antibodies.
T-cell mediated immune response
chronic HEV infection has been associated with an impaired HEV-specific T-cell response in transplant patients
However, the T-cell mediated immune response remains largely unclear in HEV infection
HEV-specific CD8+ Tcell response in chronic HEV patients was diminished in comparison to the acute disease course, but was partially restored after ribavirin therapy our patient developed chronic HEV infection which can lead to rapidly developing cirrhosis and liver failure
Treatment with ribavirin was successful in our patient but anemia as well-known side effect of ribavirin led to the discontinuation of antiviral therapy.
Currently, ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently needed.
Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
I appreciate your strategy in relation to Hep E infection and transplant.Typing whole sentence in bold or typing in capitals amounts to shouting.
SUMMARY
Background
One of the increasing causes of acute hepatitis globally now is hepatitis E with a prevalence that varies from <1% to up to 52% in Europe. There are about 5 recognized genotypes with genotype 3 being very common in Europe and transmitted zoonotically to humans. Among the immunosuppressed, acute HEV can progress to a chronic with high morbidity and mortality
Case presentation
Discussion and Conclusion
I like your your clinical approach.
Introduction:
CASE:
Discussion:
I like your well structured detailed summary and your clinical approach.
IV. Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
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Summarise this article
Background
====================================================================
Case presentation
Retrospective analysis of stored plasma samples showed the detection of HEV RNA over the last 7 months, consistent with chronic HEV infection.
====================================================================
Discussion and conclusions
===================================================================
Ribavirin is the only drug available for HEV infection, but novel treatments are needed.
Pegylated interferon alfa has antiviral activity, but cannot be used in patients with stem cell or organ transplants.
Testing for anti-HEV IgG before immunosuppression is important, diagnosing HEV infection using nucleic acid testing, counseling patients at risk, and treating HEV reinfection with ribavirin.
RT-PCR is essential for HEV diagnostics in immunosuppressed patients, but HEV antibodies do not confer universal protection.
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Well done for the role of IS in the antibody response.
Many thanks Prof.Dawlat
Introduction:
Acute hepatitis is increasingly linked to HEV infection. Five human pathogenic HEV genotypes are known, with HEV genotype 3 (gt3) dominating in Europe. HEV seroprevalence in Europe ranged from 1% to 52%. HEV gt3 is spread zoonotically to humans by eating HEV-contaminated meat. HEV infection usually causes minor, self-limiting symptoms.
Case presentation:
We report on an immunocompromised patient who, despite having high levels of antibodies, had a persistent HEV infection. During the diagnostic assessment, elevated liver enzymes led to the suspicion of HEV infection, which was confirmed by RT-PCR. We found out that the patient had been HEV RNA positive for the last seven months after doing a retrospective examination of stored blood samples. Ribavirin was able to effectively cure a chronic HEV infection in a patient.
Discussion:
Anecdotal evidence of HEV reinfection causing chronic disease is scarce. Controlling infection requires HEV antibodies. HEV antibodies have been standardized, and a minimum protective antibody concentration of 2.5 WHO units/mL is suggested. Nevertheless, a protective titer has not been determined. Choi and colleagues found that low HEV-IgG titers (< 6 IU/ml) did not protect rhesus macaques against HEV reinfection.
Conclusion:
the patient had a chronic course of HEV infection, which was effectively treated with ribavirin. This information may be found in the conclusion section. This instance demonstrates the significance of RT-PCR for HEV diagnosis in individuals with immunosuppression and lends credence to the idea that HEV antibodies may not provide universal protection against infection. It is prudent to provide counseling to individuals who are at risk for chronic HEV infection. It is important to do more research on the function that humoral and T-cell-mediated immune responses play in instances of HEV reinfection.
Thankyou.
INTRODUCTION;
Hepatitis E virus (HEV) infection is increasingly recognized as a major cause of acute hepatitis worldwide.
There are five human pathogenic HEV genotypes .
HEV genotype 3 (gt3) is the dominant HEV genotype in Europe.
HEV gt3 is transmitted zoonotically to humans and infections are linked to the consumption of HEV contaminated meat products.
In general, HEV infection remains asymptomatic or presents as mild and self-limiting disease. In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course with high morbidity and mortality rates.
Chronic HEV infection have been reported to develop in patients with detectable anti-HEV IgG before and after kidney transplantation. This suggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient.
This reported case demonstrated an immunocompromised patient who developed chronic HEV infection despite the presence of high level antibodies.
THIS ARTICLE DEMONSTRAED THE FOLLOWING IMPORTANT CLINICAL POINTS :
I.The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti- HEV IgG before the start of immunosuppressive
regimens.
II.Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
III.In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
IV.Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
V. Patient with HEV reinfection who developed a chronic course can be successfully treated with ribavirin .
Thank you.
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
Thankyou.
LOE!
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report
1- HEV incidence is increasing worldwide and constitute major cause of acute hepatitis.
2- Its route of administration by ingestion of infected meat zoonotic transmission.
3- Can be asymptomatic, or mild or severe fulminant hepatitis and can be self-limited.
4- It is 5 genotypes, genotype 3 is the most common especially in Europe.
5- Immune response started by elevation of IgM antibody in acute stage followed by appearance of IgG which decrease slowly over the time and may persist for years.
6- In immunosuppressed patient, the immune response cannot be guaranteed; also, chronic hepatitis can be developed with high morbidity and mortality.
7- HEV IgG does not offer protection against re-infection and can be increased after transplantation even if it was present pre-transplantation.
8- No definite protective titer of IgG antibodies.
Thankyou
Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection:
Introduction;
-Hepatitis E virus (HEV) infection is now recognized as a major cause of acute hepatitis worldwide.
-To date, five human pathogenic HEV genotypes are known, of which HEV genotype 3 (gt3) is the dominant HEV genotype in Europe.
-HEV gt3 is transmitted zoonotically to humans and infections are linked to the consumption of HEV contaminated meat products.
-In general, HEV infection remains asymptomatic or presents as mild and self-limiting disease.
-In immunosuppressed patients, however, acute HEV gt3 infection can progress to a chronic course (HEV RNA detectable > 6 months) with high morbidity and mortality rates.
Aim;
-Here, they report a patient who developed chronic HEV infection shortly after kidney transplantation despite the presence of high anti-HEV IgG pre- and post-transplantation.
-They describe and characterize the HEV-specific antibody response over time.
Methodology;
-They report a case who is (64-year-old man with a history FSGS underwent kidney transplantation in April 2016, who received rituximab 750 mg twice in June 2016 and therapeutic plasma exchange (26 times) with albumin and fresh frozen plasma as replacement fluid due to recurrence of FSGS, which subsequently resolved until October 2016).
-This immunocompromised patient was clinically well pre-transplantation and his physical examination was without pathological findings.
-He developed chronic HEV infection despite the presence of high level antibodies.
-HEV infection was detected using RT-PCR upon diagnostic evaluation due to increased liver enzymes. Upon retrospective analysis of stored serum samples.
Results;
-They found that the patient since 7 months was positive for anti-HEV IgG and negative for anti-HEV IgM as well as HEV RNA indicating resolved HEV infection before transplantation.
-Chronic HEV infection was successfully treated with ribavirin (200 mg , 5 doses daily).
-He received an 11- week course of ribavirin and therapy was stopped due to anemia.
-The mode of acquisition of HEV infection in this patient remains unclear; but could be related to HEV contaminated blood products, an HEV-contaminated transplant organ, or food uptake after transplantation.
Discussion;
-In current case suggests HEV reinfection and indicates that HEV antibodies did not confer protection in this patient.
-Interestingly, the rituximab induced B cell depletion might have influenced the development of HEV antibodies in this patient.
-Thus, impaired B cells in our immunosuppressed patient might have contributed to reinfection despite the presence of HEV antibodies.
-Immunosuppressive therapies might also interfere with the HEV replication cycle; that tacrolimus promoted the infection of liver cells with HEV whereas mycophenolate mofetil inhibited HEV replication and steroids showed no effect at all .
-They were able to show that the HEV-specific CD8+ Tcell response in chronic HEV patients was diminished in comparison to the acute disease course, but was partially restored after ribavirin therapy.
-Treatment with ribavirin was successful in our patient but anemia as well-known side effect of ribavirin led to the discontinuation of antiviral therapy.
-Currently, ribavirin is the only drug available for treatment of HEV infection and novel treatment strategies are urgently needed.
-Pegylated interferon-alfa has antiviral activity against HEV, however, cannot be used in patients with stem cell or organ transplants due to a high risk of rejection.
Conclusions;
-The presence of anti-HEV IgG may not be protective thus limiting the value of testing for anti-HEV IgG before the start of immunosuppressive regimens.
-Clinical work-up upon increased liver enzymes should include testing for HEV infection irrespective of the anti-HEV IgG status before immunosuppression.
-In immunosuppressed patients HEV infection should be diagnosed using nucleic acid testing.
-Counseling patients at risk for chronic HEV infection regarding the consumption of raw/ undercooked pig products seems advisable.
-The patient suffered from a chronic course of HEV infection, which was successfully treated with ribavirin.
-The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.
-This a case report study with (LOE IV)
Thankyou well done.
Summarize this article
Introduction
Case report
A 64 years old male transplanted in April due to focal segmental glomerulosclerosis (FSGS). Unfortunately had had a bad year due complications (recurrent FSGS, BKV viremia, hypogammaglobulinemia). In November 2016 developed mild transaminitis (ALT 81, AST 62, GGT 276 U/L) with normal liver ultrasounography. In March 2017 only GGT remained elevated at 215 U/L. Further tests confirmed; HEV RNA PCR , anti-HEV IgM & IgG were positive. His stored plasma sample over the previous 7 months was positive for HEV RNA but samples taken before transplantaion was positive for anti-HEV IgG and negative for both HEV RNA PCR and anti-HEV IgM i.e., resolved HEV infection. Genotying showed gt3 and he was treated for around 3 months by ribavirin 200g 5 times /day in September 2017. Ribavirin was discontinued due to anemia but his viral load was undetectable and treated successfully. It was not clear how he acquired HEV and possibilities may be contaminated food or the transplanted organ.
Take home messages
Well done well understood and demonstrated.
Thnx prof
HEV – 5 genotypes
gt3 most dominant in Europe.
HEV seroprevalence 1% to 52%
transmitted via consumption of contaminated meat products.
HEV infection –
asymptomatic
mild or self limiting disease
infection fl b rise in anti HEV Ig M flb rise in Ig G, which then slowly declines.
In immunosuppressed patients acute HEV gt3 can progress to Chronic HEV, which is HEV RNA detectable > 6 months.
Case
64 yr old man
F S G S ~ native kidney disease
Post Tx in April 2016 on Tac, MMF, prednisone.
In June 2016, F SGS recurrence – 2 dose of Rituximab and 26 session of plasmapharesci done.
Had BK viraemia
Prednisone tapered to 10 mg lday
MMF reduced to a dose of 250 mg BD
settled
In November 2016 AST 62 U/L
USG – normal
March 2017
AST-44, ALT -45 but gamma GT 215
USG abdomen – normal
Hep C RNA –
HEV RNA detected
HEY Ig M and Ig G positive
HEV RNA positive in retrospective samples from 7 months.
So chronic HEV.
genotype was 3c.
pre transplant sample showed HEV Ig G +
Treatment
Ribavirin 200mg 5 times daily for 11 weeks
HEV RNA became negative and remained so.
Liver enzymes became normal.
Discussion
Case of HEV reinfection inspite of HEV Ig G + pre transplant.
low anti – HEV <7 WHO units/ ml did not protect against reinfection.
Also surprising was initially Ig G showed rapid rise f/b Igm.
Also impaired B cells clue to Rituximab contributed.
IgG Titre decreased post Tx due to immunosuppression.
Tacrolimus promotes HEV infection of liver cells, MM F prevents.
HEV specific CD8+ Tcell response in chronic HEV patients was diminished, which was partially restored by Ribavirin therapy.
Treatment with Ribavirin was successful but needed to be stopped due to anaemia.
Summary
anti Ig G HEV may not be protective.
test For HEV when liver enzyme deranged
Diagnose HEV using NAT
Advise against consuming raw/ undercooked pig products.