S. Dharancy, V. Crombe, M.C. Copin, E. Boleslawski, L. Bocket, N. Declerck, V. Canva, A. Dewilde,P. Mathurin, and F.R. Pruvot

Fatal Hemophagocytic Fatal Hemophagocytic Syndrome Related to Human Syndrome Related to Human Herpesvirus-6 Reinfection Herpesvirus-6 Reinfection Following Liver Following Liver Transplantation: A Case ReportTransplantation: A Case Report

Case report: A 49y old woman underwent liver-kidney transplant in

07/2005 for polycystic liver kidney disease, with CRF and PHTN due to venous outflow obstruction.

Primary immunosuppression: induction therapy with basiliximab (20 mg on D0 and D4), & steroids (pred 10 mg/kg/d for 3 days, then 20 mg/d), MMF (500 mg tid), and cyclosporine (250 mg bid).

Graft function was unremarkable, and Liver graft biopsy showed slight steatosis, with no

ischemia-reperfusion damage. On day 12, sudden fever at 38°C and extensive skin rash. No pathogen was found in repeated blood or urine

cultures, and chest X ray was normal. All other bacterial, fungal and viral screenings were negative. CMV antigen was undetectable.

Clinical progress:….

Empiric broad-spectrum antibiotics were ordered. The clinical condition deteriorated with neurological

s/s with confusion; & lung infiltrates with severe hypoxemia requiring mechanical ventilation.

On day 19, leukopenia and thrombopenia were detected, with liver dysfunction and severe hyponatremia at 112 mEq/L. A bone marrow biopsy showed erythro- and thrombophagocytosis leading to the diagnosis of hemophagocytic syndrome.

The patient died on postoperative day 23 from multi-organ failure.

Clinical course demonstrating progressive cytopenia with falling WBC and platelets counts after an initial peak. And the Favtor V levels and creatinine levels represent eventual muliple organ dysfunction.

Autopsy findings: At autopsy, the spleen, bone marrow, and liver

showed numerous activated macrophages engulfing erythrocytes and leukocytes, without lymphoid malignancy.

Specific HHV-6 polymerase chain reaction (PCR) did not detect HHV-6 prior to transplantation during the screening period and in the early postoperative period (day 9 after LT).

But, the patient had a viral load at 21,254 copies/g of DNA on day 20.

Serological analysis showed positivity for IgG before transplantation, proving the existence of a previous infection.

Hemophagocytosis in liver and bone marrow:phagocytosis by macrophages of erythrocytes and leukocytes(arrows)

About HHV-6:- HHV-6 causes exanthema subitum (roseola infantum),

febrile seizures and other infectious syndromes of early childhood. In adults, there is a high sero-prevalence of 90-95% and primary infections are uncommon.

Two variants of HHV-6 have been categorized: HHV-6A and HHV-6B.

After primary infection, HHV-6 persists for life, and is shed in saliva and transmitted to others, and may reactivate during immunosuppression.

HHV-6 is ubiquitous, with more than 95% of adults being seropositive (geographic differences vary between 70 and 100%). HHV-6 infects over 90% of people within the first two years of life.

Most HHV-6 infections are asymptomatic or very mild, and about 80% of them without any clinical symptoms.

HE-stained sections of cervical lymph node from a pt. Paracortical areas containing atypical cells with large, eosinophilic, nuclear, and/or cytoplasmic inclusions, suggesting viral etiology. Immunostaining for HHV-6 shows positive atypical cells. Cytoplasmic inclusions +. Immunohistochemical stains reveal that atypical cells (arrows), are positive for CD3 and CD4 and negative for CD8. H&E-stained section of the liver biopsy from a patient demonstrating viral inclusions.

HHV-6 in Transplantation It is generally agreed that most adult transplant recipients

are seropositive for HHV-6 prior to transplant, & that HHV-6 reactivates to an active infection in approximately 50% of the patients relatively early after transplant, i.e. during the first 2 to 4 weeks after transplant.

The data on clinical manifestations in these patients are not subject to such a clear consensus………..

Some investigators have concluded that the HHV-6 reactivations cause significant clinical disease (bone marrow suppression and CNS disease), while other authors have failed to observe such disease associations. The severity of disease varies along the whole spectrum from mild febrile illness, leukopenia to fulminant encephalitis.

Seroepidemiological studies have shown that 20% to 40% of liver transplant recipients develop active HHV-6 infection.

The virus is usually detected in the absence of clinical manifestations or organ involvement, although when symptomatic, clinical conditions include fever, bone marrow suppression, and skin rash.

After SOT, HHV-6 has been more frequently associated with encephalitis, & also other infections including cytomegalovirus (CMV), organ rejection and mortality.

However the exact pathogenesis of HHV-6 remains to be defined. (HHV-6 is known to be lymphotrophic and neurotrophic, with the ability to infect a multitude of cell types).

HHV-6 in solid organ transplants:• In prospectively studied liver transplant patients, 50% were

positive for HHV-6 infection by virus isolation from blood within 5 weeks of transplant, and 60% of these virus positive patients showed concurrent fever, 40% showed associated thrombocytopenia, and 20% developed associated mental status changes (N Singh et al).

• In a more extensive prospective study of liver transplant patients (Chang FY, 1999), HHV-6 reactivations accounted for 80% of the cases of idiopathic leukopenia and were the predominant cause of febrile illnesses after transplant.

• Data suggests that the incidence of HHV-6 associated disease ranges from approximately 30% to 60% in patients who are actively viremic, an incidence similar to that observed with CMV (Meyers et al).

Time-related appearance of HHV-6, HHV-7 and CMV antigenemia:

The problem:…..

There is still some uncertainty as to the precise role that this virus plays in causing the associated clinical outcomes following transplantation….. This uncertainty probably reflects the persistent nature of HHV-6 infection.

HHV-6 infections cause fever, bone marrow suppression (esp in bone marrow transplants) and CNS disease in both BMT and solid organ transplant patients and is a cause for specific morbidity and mortality.

Data is complicated by the facts that different types of transplant recipients vary widely with respect to their degree of immuno-suppression, that transplantation protocols vary between different programs and institutions, and that different diagnostic procedures have been applied to patient samples

HHV-6 infection in transplant patients is usually asymptomatic but complications have also been reported. HHV-6 may cause fever and other symptoms, neurological disorders, graft dysfunction, pneumonitis and hepatitis (Herbein, 1996, Humar, 2002, Lautenschlager, 1998, Ljungman,2000, Singh, 1997, Yoshikawa, 2002, Zerr , 2001).

In addition to the direct effect of HHV-6, indirect effects also have been recorded. HHV-6 is considered an immunomodulatory virus that may facilitate superinfections with other opportunistic infections (Flamand et al. 1995, Singh et al. 1997). HHV-6 reactivations are often associated with rejections and CMV infections (Dockrell et al. 1997, Griffiths et al. 1999, Lautenschlager et al. 1998).

Hemophagocytic syndrome: disorder of immune regulation, characterized by a widespread proliferation and multisystemic infiltration of macrophages that result in uncontrolled hemophagocytosis in bone marrow and/or reticulo-endothelial system, and hence cytopenias.

Diagnosis:• Current serologic tests are based on either

immunofluorescence or enzyme immunoassays, and

are not adequately sensitive or specific• Antigenic cross-reactivity between HHV-6 and CMV

remains unclear .• The virus often cannot be isolated from PBMCs. The

poor results of cultures for HHV-6 could reflect the scarcity of active viral replication in most subjects, which would make its detection more clinically meaningful.

• PCR is more sensitive than culture for the detection of HHV-6.

• Quantitative PCR may help define the border between latency and active viral replication.

Treatment:

• Gancyclovir.• Foscarnet.• Cidofovir.

Thus…• A high index of suspicion would be critical.

• All patients with

- skin rash.

- leukopenia/ unexplained cytopenia.

- CNS signs and symptoms/ convulsions.

- unexplained fever.

should be screened for HHV-6 infection.

• Isolation of the virus from cell free fluids; and quantitative PCR on peripheral blood mononuclear cells are representative of active infection.

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