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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2011  |  Volume : 22  |  Issue : 1  |  Page : 107-111
Fulminant hepatitis following primary herpes simplex virus infection in renal transplant recipients

1 Renal Transplant Unit, Royal Free Hospital, London, UK
2 Virology Unit, Royal Free Hospital, London, UK

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Date of Web Publication30-Dec-2010


Fulminant hepatic failure (FHF) is a rare but well-recognized complication of pri­mary herpes simplex virus (HSV) infection in immunocompromised patients. Here, we report two cases of acute hepatitis and FHF secondary to primary HSV type 1 infection following renal transplantation in the absence of any mucocutaneous manifestation. High levels of HSV type-1 DNA were detected in the blood. Both patients were seronegative for HSV 1 and HSV 2 immuno­globulin G (IgG) before transplantation, whereas the donor of patient 1 was HSV 1 IgG-positive but had no viremia and the donor of patient 2 was HSV-seronegative. Patient 1 recovered with acyclovir and immunoglobulin whereas patient 2 did not respond and succumbed to death. HSV­seronegative patients are potentially at risk of developing severe primary HSV disease following transplantation, particularly in the absence of routine anti-viral prophylaxis. HSV infection should always be excluded in transplant patients with hepatic dysfunction.

How to cite this article:
Al Midani A, Pinney J, Field N, Atkinson C, Haque T, Harber M. Fulminant hepatitis following primary herpes simplex virus infection in renal transplant recipients. Saudi J Kidney Dis Transpl 2011;22:107-11

How to cite this URL:
Al Midani A, Pinney J, Field N, Atkinson C, Haque T, Harber M. Fulminant hepatitis following primary herpes simplex virus infection in renal transplant recipients. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2021 May 12];22:107-11. Available from: https://www.sjkdt.org/text.asp?2011/22/1/107/74376

   Introduction Top

Herpes simplex virus (HSV) is a common worldwide pathogen that establishes life-long latency following primary infection. [1] In immu­nocompromised patients, it can be associated with disseminated disease and fulminant he­patic failure (FHF) from primary and reacti­vated infection. We report two cases of FHF secondary to primary HSV infection following deceased donor renal transplantation. The first patient was treated successfully with intra­venous (IV) acyclovir and immunoglobulin (IVIG). This patient recovered both liver and renal function post-treatment. However, the second patient who was also treated with IV acyclovir died from FHF.

   Case Reports Top

Case 1

A 26-year-old woman with end-stage renal failure secondary to familial focal and seg­mental glomerulosclerosis (FSGS) underwent uneventful renal transplant surgery from a deceased donor. Her pre-transplant serology showed the presence of specific IgG against Epstein-Barr virus (EBV) and varicella zoster virus (VZV), but not against cytomegalovirus (CMV), HSV 1 or HSV 2. However, her donor was seropositive for both CMV and HSV 1. Fol­lowing the transplant surgery, she was monitored twice-weekly for CMV DNA and weekly for EBV DNA in whole blood by polymerase chain reaction (PCR) assays and, according to the unit protocol, she was not given any anti-CMV prophylaxis.

The patient received anti-CD25 monoclonal antibody for induction and prednisolone, tacro­limus and mycophenolate mofetil (MMF) for maintenance immunosuppression. Post-opera­tively, the grafted kidney was functioning well and the serum creatinine level decreased to 95 μmol/L. Two weeks post-transplantation, she developed a fever of 37.9°C with no obvious focus of infection and her physical examina­tion was unremarkable. Multiple blood cul­tures were negative and a computed tomo­graphy (CT) scan of her abdomen and pelvis did not demonstrate any intra-abdominal or pe­rinephric collection. Three days later, her ala­nine aminotransferase (ALT) and aspartate amino-transferase (AST) started to rise and she continued to rapidly deteriorate. This was as­sociated with an initial rise in white cell count and CRP, with an associated thrombocyto­penia. She developed right upper quadrant ten­derness and guarding. A triple-phase liver pro­tocol CT scan revealed multiple low-density lesions with-in the liver suggestive of micro­abcesses [Figure 1]. MMF was stopped as she became septic and she was commenced on IV, aciclovir meropenem, ciprofloxacin, teicoplanin and amphotericin.
Figure 1: Triple phase CT scan: showing inumerable small, low-density lesions within the liver. These are in keeping with micro abscesses.

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She rapidly became hypoxic and encephalo­pathic and was transferred to the intensive care unit for ventilatory support. With worsening renal function, she became oliguric and re­quired continuous veno-venous hemofiltration (CVVHF). A laparoscopic liver biopsy [Figure 2]A showed necrotic areas in the liver contai­ning inflammatory infiltrates with "glassy" nu­clei around the necrotic areas. Immunopero­xidase staining and PCR of the biopsy tissue was positive for HSV [Figure 2]B. A quantita­tive real-time PCR detected high levels of HSV DNA in the blood (levels >10.4 log10 copies/ mL; [Figure 3]). [2] Blood PCR for CMV, EBV, VZV, HHV6, adenovirus and enterovirus was negative. The patient was started on intra­venous acyclovir (5 mg/kg bd) 2 days before diagnosis and received intravenous immuno­globulin (IVIG) for 10 days.
Figure 2A: Liver biopsy H&E. Some hepatocytes around the necrotic areas contain "glassy" nuclei, and there are occasional multinucleate cells. Elsewhere there are scattered apoptotic bodies.
Figure 2B. Immunoperoxidase staining for HSV.

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Figure 3: Figure 3. Kinetics of herpes simplex virus (HSV) type-1 viraemia in Case 1. HSV 1-specific IgG was detected in serum ~5 weeks after the initial DNA detection.

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There was a rapid response to treatment [Figure 4]. However the renal function con­tinued to deteriorate rapidly. She had weekly renal transplant biopsy X 4, which correlated with acute tubular necrosis (ATN), and the im­munoperoxidase staining for HSV was nega­tive in all the biopsies. She made a good res­ponse to acyclovir, IVIG and the reduction of her immunosuppressive drugs. Despite the ra­pid recovery of liver function tests and con­tinued IV acyclovir, her blood HSV PCR le­vels remained elevated [Figure 3]. However, she developed HSV 1-specific IgG 5 weeks after her initial primary HSV diagnosis and her HSV DNA in the blood eventually became un­detectable after 4 months. Retrospective PCR testing on stored blood samples from the pa­tient taken on the day of transplant and from the donor did not detect any HSV DNA (level of detection, 100 copies/mL).
Figure 4: Response to treatment in Case 1. Rapid improvement in AST following treatment with IV aciclovir.

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Case 2

A 59-year-old man with autosomal-dominant polycystic kidney disease, maintained on hemo­dialysis for 5 years, was admitted to the hospital for deceased donor renal transplantation. The patient was seronegative for HSV 1 and 2 before transplantation. Standard immunosup­pression was commenced pre-operatively as with our first reported case.

Post-operatively, the patient required inotropic support for 3 days in the intensive care unit as he became hypotensive during the operation and his blood pressure persistently dropped when trying to wean him off in the recovery room despite adequate intravenous infusion. Bilateral basal lung collapse was noted on chest radiography and intravenous amoxicillin and clavulanic acid were continued post-ope­ratively. On day 10 post-op, significant clinical improvement occurred; the patient started to show neurological response, urine output was >750 mL per day, CRP started to fall and re­nal biopsy showed no evidence of acute rejec­tion. However, liver function was noted to be elevated for the first time (ALP, AST and ALT were 124, 128 and 114 U/L, respectively, and the prophylactic trimethoprim and sulfametho­xazole were suspended). Within the next 48 hours, he became acutely unwell; pyrexial and clinically septic, with deteriorating graft func­tion and a significant clotting diathesis. There was no evidence of any herpetic lesions. Liver function tests implied acute and overwhelming hepatocyte lysis (peak values on day 13 post-op: ALP, AST, ALT and y-GT were 319, 11037, 2554, 369 U/L, respectively). Hepatic CT and ultrasound demonstrated a liver with normal appearance, all vessels patent and no evidence of necrosis or infarction. Pending repeat viral serology and PCR, empirical intravenous acy­clovir was commenced on day 13. Antibiotics were stopped and the immunosuppression re­gime was moderated. On day 14, the patient became frankly encephalopathic, with profuse melena, and died later on the same day.

The PCR detected high levels of HSV-1 DNA in the blood. There was no evidence of seroconversion, with no detectable IgG against HSV. The kidney donor had no serological indication of HSV 1 or 2 infection. Our evi­dence is therefore consistent with a primary HSV I infection causing hepatitis and fulmi­nant hepatic failure, but the source of infection remains unclear.

   Discussion Top

HSV is a very commonly acquired viral in­fection and has two types. Type 1 is often limi­ted to the oral mucosa and type 2 manifests as genital lesions. [1] In general, HSV produces a mild, self-limiting hepatitis in immunocompe­tent patients. Primary infection in neonates, pregnant women and immunosupressed patients can lead to FHF without skin lesions. [3]

Systemic HSV as a cause of fulminant hepa­titis post-transplantation was reported for the first time in 1976 by Holdsworth et al, where their case failed to respond to an infusion of cytosine arabinoside and proved fatal. In 1980, Eliot et al reported two additional fatal cases that occurred in renal transplant recipients; in their first case, there was evidence that the allograft might have been the source of infec­tion and in their second case, the patient was found to have disseminated infection from a genital ulcer and failed to respond to vida­rabine therapy, despite being started at an early stage of the clinical course. Norvell et al in 2007 analyzed the published literature of her­pes simplex viral hepatitis. They found that most cases were first diagnosed at autopsy (58%) and, from all the reports, only 30% were immunosuppressed transplant patients. It remains unclear why one-quarter of the pa­tients who were considered immunocompetent progressed to FHF. [4] Overall, 74% of the pub­lished cases progressed to death and 57% required a liver transplant. [5]

HSV infection most commonly results from reactivation of the latent virus in individuals who are HSV-seropositive at the time of trans­plantation; [6] both our cases were seronegative pre-transplantation. The donor in the first case was HSV 1-seropositive and, therefore, the donor kidney itself could have been the source of HSV transmission. However, this could not be confirmed as the donor was aviremic and, without a comparison of the two virus strains, other sources could not be ruled out. Koneru et al described two patients who received renal transplants from the same donor in 1988; both patients died from FHF secondary to HSV. [7] Donor kidneys have since been thought as a potential source of HSV infection. The donor in our second case was reported as HSV 1 and 2-seronegative; the source of infection in this case remains unclear. However, this is likely to be from exogenous sources on the ward.

The clinical presentation in most cases in the literature is fever (98%), with absence of skin lesions (56%). [5] The absence of clinical signs makes the diagnosis of HSV difficult, and de­lays treatment. Hence, early clinical suspicion of HSV in a febrile patient is an important factor to improve the outcome. It was noticed that coagulopathy, thrombocytopenia and leuko­penia are common laboratory findings (more than 70% of the cases). ATN secondary to liver failure was reported in almost 65% of the HSV hepatitis patients. [5]

All studies demonstrated that PCR testing of blood samples could establish the diagnosis by non-invasive methods as HSV DNA has been positive in both our cases. However, most cen­ters do not have access to rapid molecular tests and, often, the diagnosis is made after the pa­tient has developed FHF. [5]

Despite the frequent fatal prognosis in the literature, HSV is one of the few treatable cau­ses of FHF. HSV is very sensitive to acyclovir and treatment is effective with easy adminis­tration. It is clear that early diagnosis and, more importantly, clinical suspicion and early treat­ment are key features in improving patient survival. In the first patient who was successfully treated, cessation of all immunosuppre­ssion, apart from steroids and the addition of IVIG as part of the antiviral treatment, resulted in response to acyclovir without permitting transplant rejection.

Routine CMV prophylaxis with valganciclovir offers partial protection against HSV. [8] How­ever, in units that practice CMV monitoring and pre-emptive CMV therapy, HSV serone­gative patients may potentially be at risk of developing severe primary HSV disease. We routinely screen our patients for HSV IgG pretransplant and, following these two cases, now add valaciclovir prophylaxis for HSV-serone­gative patients. This may need to be a standard practice if CMV prophylaxis is not used.

   References Top

1.Rosenthal SL, Stanberry LR, Brio FM, et al. Seroprevalence of herpes simplex virus type 1 and 2 and cytomegalovirus in adolescents. Clin Infect Dis 1997;24:135.  Back to cited text no. 1
2.Jerome K, Huang M, Wald A, Selke S, Corey L. Quantitative stability of DNA after extended storage of clinical specimens as determined by real-time PCR. J Clin Microbiol 2002;40:2609-11.  Back to cited text no. 2
3.Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 1997;337: 1105.  Back to cited text no. 3
4.Ichai P, Roque Afonso AM, Sebagh M, et al. Herpes simplex virus-associated acute liver failure: A difficult diagnosis with a poor prog­nosis. Liver Transplant 2005;11(12):1550-5.  Back to cited text no. 4
5.Norvell J, Blei A, Jovanovic BD, et al. Herpes simplex virus hepatitis: An analysis of the published literature and institutional case. Liver Transplant 2007;13:1428-34.  Back to cited text no. 5
6.Nebbia G, Mattes FM, Ramaswamy M, et al. Primary herpes simplex virus type 2 infection as a cause of liver failure after liver trans­plantation. Transpl Infect Dis 2006;8:229-32.  Back to cited text no. 6
7.Koneru B, Tzakis A, DePuyet L, et al. Transmission of fatal herpes simplex infection through renal transplantation. Transplantation 1988;45(3):653-6.  Back to cited text no. 7
8.Sliflan M, Doron S, Snydman DR. Viral pro­phylaxis in organ transplant patients. Drugs 2004;64(24):2763-9.  Back to cited text no. 8

Correspondence Address:
A Al Midani
Assad University Hospital, Damascus, Syria

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