Bone Marrow Transplantation – Varicella zoster virus reactivation after autologous SCT is a frequent event and associated with favorable outcome in myeloma patients

Bone Marrow Transplantation - Varicella zoster virus reactivation after autologous SCT is a frequent event and associated with favorable outcome in myeloma patients

Herpesvirus infections are among the most common and debilitating opportunistic infections in patients with acquired immunodeficiency syndrome (AIDS), and they may have atypical clinical features. Primary infection causes varicella (chicken pox), after which virus becomes latent in cranial nerve ganglia, dorsal root ganglia, and autonomic ganglia along the entire neuraxis. We generated 251 monoclonal antibodies (MAbs) against 59 of the 71 (83%) currently known unique VZV proteins to characterize VZV protein expression in vitro and in situ. It is possible that aerial transmission originates from symptomless oral lesions. The results were obtainable within 5 h and were in agreement with the results achieved by immunofluorescence tests or by virus isolation when positive. Thus, data are largely missing on the incidence of HZ in myeloma patients after ASCT treated with current induction regimens. The VZV genome copy number was 7.1 x 10(7) to 8.0 x 10(8) copies per 10(5) cells, and infectious virus was recovered.

In this analysis, we report on the incidence and the subjective disease burden of HZ in a large single-center cohort of consecutive myeloma patients uniformly treated with high-dose melphalan and ASCT in first remission while applying a consistent restrictive oral antiviral prophylaxis. We also aimed to identify myeloma patients at an increased risk of developing HZ after ASCT. Finally, no data are available so far on the prognostic significance of HZ in myeloma patients, and this study intended to clarify this issue. This is a single-center study investigating all consecutive adult multiple myeloma patients in first remission undergoing high-dose melphalan chemotherapy followed by autologous SCT between January 2005 and December 2011 at the University Hospital Bern, Switzerland. The mechanism(s) by which VZV causes pathological vascular remodeling can be surmised from studies of VZV-infected arteries from patients with virologically confirmed VZV vasculopathy. During primary infection, VZV establishes latency in sensory trigeminal and dorsal root ganglia. In immunocompetent individuals, it is probably due to the decline effectiveness of previously acquired immunity with advancing age.
Bone Marrow Transplantation - Varicella zoster virus reactivation after autologous SCT is a frequent event and associated with favorable outcome in myeloma patients

A suspected case of HZ was defined as a new-onset rash characteristic of HZ (unilateral, dermatomal and accompanied by pain broadly defined to include allodynia, pruritus or other sensations), or a vesicular rash suggestive of VZV infection regardless of the distribution and no alternative diagnosis. Specific laboratory findings strongly suggesting HZ comprised vesicular swabs positive for VZV by PCR, culture or immunohistochemical staining. Postherpetic neuralgia was defined by the presence of HZ-associated ‘worst’ pain persisting or appearing after onset of a HZ rash. Prospectively stored blood samples taken during stem cell collection immediately preceding ASCT were analyzed together in 2013 using the Serion ELISA classic VZV IgG test kit (Institut Virion, Serion GmbH, Wuerzburg, Germany) and the immunofluorescence assay (Merifluor VZV IgG IFA kit, Meridian Bioscience Inc, London, UK) for the detection of VZV specific IgG antibodies by the indirect fluorescent antibody approach according to the manufacturer’s instructions. The immunofluorescence test to determine the VZV status is based on dilution of the patient serum: absence of fluorescent cells at the dilution of 1:10 was counted as negative, reactions at 1:10 or 1:20 were considered borderline, and serum positive at 1:40 dilution or greater was considered positive. Two independent investigators analyzed all samples by microscopy, and positive and negative controls were run in parallel. The Serion Elisa classic VZV IgG test is based on the ELISA method.

Although the exact incidence of VZV vasculopathy is unknown, recent studies from the United Kingdom, Europe, and Asia have indicated that stroke after zoster is not uncommon. However, the increased incidence of HZ-related complications within the expanding elderly population calls for more effective ways to prevent primary infection with VZV and to limit reactivation from latency. Varicella is highly communicable, with an attack rate of 90% in close contacts. Until December 2006, myeloma patients received four cycles of vincristin, adriamycin and dexamethasone remission induction (vincristine, doxorubicin and dexamethasone). Since 2007, patients received thalidomide and dexamethasone, and since 2009, a bortezomib- and dexamethasone-based induction regimen was used. For mobilization of PBSCs, high-dose cyclophosphamide and G-CSF were used until 2005; since 2006, it was replaced by vinorelbine chemotherapy together with G-CSF. Melphalan 200 mg/m2 was used for high-dose chemotherapy, and at least 2 × 10^6 CD34+ cells per kg body weight were re-infused.

Antiviral prophylaxis comprised 500 mg of oral acyclovir twice daily starting on the first day after ASCT and continued for 3 weeks. In patients with limiting oral mucositis, temporary interruption of oral acyclovir treatment or change to intravenous administration was decided on an individual basis. Oral antifungal prophylaxis with fluconazole 400 mg once a week and PcP prophylaxis with trimethoprim/sulfamethoxazole three times a week were given for 3 weeks. No routine antibiotic prophylaxis was administered.

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