This case report describes a fatal hemophagocytic syndrome in a 49-year-old woman following liver transplantation that was related to a human herpesvirus-6 (HHV-6) reinfection. The patient underwent liver-kidney transplantation and had an unremarkable post-operative course until developing a fever and rash on day 12. Her condition deteriorated with neurological symptoms, lung infiltrates, and multi-organ failure. Bone marrow biopsy revealed hemophagocytosis, and autopsy showed numerous activated macrophages engulfing blood cells. HHV-6 PCR was negative early after transplant but detected on day 20, showing reactivation. The reactivation of HHV-6 led to hemophagocytic

1. S. Dharancy, V. Crombe, M.C. Copin, E.
Boleslawski, L. Bocket, N. Declerck, V.
Canva, A. Dewilde,
P. Mathurin, and F.R. Pruvot
Fatal HemopHagocyticFatal HemopHagocytic
Syndrome related to HumanSyndrome related to Human
HerpeSviruS-6 reinFectionHerpeSviruS-6 reinFection
Following liverFollowing liver
tranSplantation: a caSetranSplantation: a caSe
reportreport

2. 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.

3. 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.

4. 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.

5. 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.

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

7. 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.

8. 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.

9. 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.

10.  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).

11. 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).

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

13. 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

14.  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.

15. Diagnosis:
• Current serologic tests are based on either
immunofluorescenceor enzyme immunoassays, and
are not adequately sensitive or specific
• Antigenic cross-reactivity between HHV-6 andCMV
remains unclear .
• The virus often cannot be isolatedfrom PBMCs. The
poor results of cultures for HHV-6could reflect the
scarcity of active viral replication in mostsubjects,
which would make its detection more clinically
meaningful.
• PCR ismore sensitive than culture for the detection of
HHV-6.
• Quantitative PCR may help define the border
between latency and active viralreplication.

16. Treatment:
• Gancyclovir.
• Foscarnet.
• Cidofovir.

17. 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.

18. THANK YOU!