Ariza-Heredia et al. published an interesting review of HHV8
associated complications in Transplantation this month. The review, of which the major points are
highlighted below, cover the pathogenesis, epidemiology, clinical presentation,
diagnosis and treatment, and prevention of HHV-8.
Pathogenesis of HHV-8
After primary infection HHV-8 establishes latency in CD19 B
cells. It can exist in a latent phase and
beinduced to transition to the lytic state.
The trigger of this transition is unknown, however, once in the lytic
phase several genes are upregulated increasing the progression of the cell
cycle, Bcl-2 protien preventing apoptosis, secretion of IL6 (promotes B-cell
proliferation) and angiogenic cytokines which stimulate VEGF.
Epidemiology and Risk Factors.
Seroprevalence ranges from 4-7% in the U.S. to 5-20% in the
Mediterranean and > 50% in zones of Africa and Amazon basin. The solid organ transplant population in the
U.S. has been shown to have a higher rate
of seropositivity (15%). The chance of
developing an HHV-8 related complication is highest among patients from
countries with a high seroprevalence rate.
Infection can occur from reactivation of latent infection or primary
infection. Transmitting via organ
transplant has also been reported.
Clinical presentation
Primary infection in immunocompromised patients is often characterized
by fever, splenomegaly, rash, lymphoid hyperplasia and pancytopenia – similar
to many other viral infections. Other
classically associated diseases include Kaposi’s Sarcoma, Primary Effusion
Lymphoma (PEL)and Castleman’s
disease. In solid organ recipients the
incidence is greater in patients who are males, older age, travel or reside in
Africa or the Middle East, are mismatched at the HLA-B locus and who have been
treated with antilymphocyte globulin. In the US the incidence has been reported as
8.8 cases/ 100,000 person years. KS most
commonly affects the skin (90% of cases) whereas visceral involvement occurs in
only about 25% of kidney transplant recipients.
PEL is a rare form of non-Hodgkin’s lymphoma which can either present as
lymphomatous involvement of serosal serfaces (classic PEL) or tissue-based
tumors with a poor prognosis (solid PEL).
Cells can be HHV-8 postitive or HHV-8/EBV double-positive. Only few case reports have been documented in
solid organ recipients. Castleman’s
disease is characterized by IL-6 overexpression which results in lymph node
hyperplasia either unicentric, or multicentric.
Patients usually present with lymphadenopathy, effusions, higher fevers
and may even has concomitant KS lesions.
Again, this complication is very rare in solid organ transplant
recipients.
Diagnosis
Serology has limited utility. Antibodies can be detected against the latent
phase antigen LANA-1 or the lytic antigen (ORF65 and K8.1) which correlate
better with high HHV-8 viral loads. HHV-8
DNA quantification in plasma and PBMC’s can also be performed. In addition, immunohistochemical staining can
be performed on human tissue confirming active infection.
Treatment
The major treatment of HHV-8 is reduction of total
immunosuppression. Sirolimus also has
been used for the treatment of KS and other HHV-8 disease. If there is no improvement with the above strategies
chemotherapy such as CHOP has also been employed. Castleman’s disease can be cured with
surgical excision if unicentric, while treating multicentric disease may entail
therapy with rituximab, anti-IL6 receptor antibodies and antiviral medications. Of the antiviral agents, ganciclovir,
foscarnet and cidofovir have in vitro activity against HHV-8 making them a potential
treatment or prevention modality. Unfortunately
good in vivo and prospective data on treatment and prevention does not
exist.
In summary, HHV-8 is
an important etiologic agent for transplant associated complications/
malignancies especially for those from endemic regions. A variety of diagnostic and therapeutic
treatments exist though recognition of the clinical syndrome and reduction of
immunosuppression remain the cornerstones of treatment.
Post by Dr. Vinay Nair
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