Oral Mucositis After Allogeneic Hematopoietic Stem Cell Transplantation: Important Impact Of The Presence Of Aciclovir-Resistant Herpes Simplex Virus (HSV-1) On Its Occurrence
Authors: Frobert Emilie , Sobh Mohamad , Morfin Florence , Labussiere Helene , Ducastelle Sophie , Gilis Lila , Barraco Fiorenza , Escuret Vanessa , Thomas Xavier , Nicolini Franck E. , Lina Bruno , Michallet Mauricette 
Published: October 2019

Abstract

Introduction
Oral mucositis (OM) is a frequent and serious complication seen in 60-90% of patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT), decreasing patient's quality of life and increasing the occurrence of opportunistic infections. Many studies have evaluated OM occurrence according to the intensity of conditioning regimen with discordant conclusions. After transplantation, various viral loads can be reactivated, among them, the Herpes Simplex Virus 1 (HSV-1). HSV-1 can induce ulcers in the mouth floor , buccal and labial mucosa, lateral side and tip of the tongue, and soft palate and may aggravate mucositis. It is unknown whether prolonged HSV-1 presence in allo-HSCT recipients despite antiviral treatment is caused by the profound immunosuppressed status of HSCT recipients, or due to resistance of the virus to the antiviral medication. Very few recent studies have demonstrated that the HSV-1 positivity and resistance to antiviral treatment represent significant risk factors associated to OM. The aim of our study is to evaluate the incidence and impact of HSV-1 despite antiviral treatment during allo-HSCT on the OM occurrence.

Patients and methods
We evaluated 62 patients who underwent allo-HSCT for hematological malignancies at our department between 2007 and 2011 for whom culture detection of HSV-1 in throat swab was positive, susceptibility of the virus to antiviral treatment (aciclovir) and assessment for OM was performed. There were 33 males and 29 females with a median age of 48 years (range:18-63), 35% received myeloablative conditioning, 31% received a reduced intensity conditioning and 34% received FLAMSA sequential conditioning (Schmid C et al. JCO 2005). As cell source, 35% received bone marrow, 46% received peripheral blood and 19% cord blood; 44% were in complete remission (CR) at transplantation, all patients received antiviral prophylaxis (aciclovir) before transplantation. The GVHD prophylaxis consisted mainly of cyclosporine A plus mycofenolate mofetil.

Results
After transplantation, all patients engrafted, 73% had an aplasia duration longer than 3 weeks, 84% had infections overall among them 48% were viral. The medical assessment showed 43 (69%) patients with OM, 13 (30%) grade I, 15 (35%) grade II, 8 (19%) grade III and 7 (16%) grade IV. Sensibility tests revealed the presence of HSV-1 resistant to aciclovir in 26 (42%) patients. The multivariate analysis on OM occurrence taking into account patients age, disease status at allo-HSCT, conditioning type, cell sources, aplasia duration and the presence of resistant HSV-1 showed a significant impact of the following factors: Disease status (CR) [HR=0.2 (0.05-0.6), p=0.004], FLAMSA regimen [HR=3.1 (1-10), p=0.05] and the presence of resistant HSV-1 [HR=15 (0.8-129), p=0.02].

Conclusion
We demonstrated that patient not in CR at transplantation or having FLAMSA regimen experience higher rates of OM. More importantly, having a resistant HSV-1 represents a higher risk for OM development, this occurs even under antiviral prophylaxis leading to the need of better antiviral strategies.

Disclosures:
No relevant conflicts of interest to declare.