Wednesday, October 19, 2011

HHV-8 in Transplantation

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. 
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. 
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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