Abstract

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Introduction:



Here we present the case of a 56-year-old human immunodeficiency virus (HIV)-infected man with multiple anal condylomas and positivity for human papilloma virus (HPV) 18 on anal brushing. Biopsies of the anal mucosa led to the diagnosis of Bowen's disease and a subsequent pelvic magnetic resonance imaging (MRI) scan evidenced multiple reactive lymphoadenopathies and large intra-anal condylomas. The patient was treated with a complete excision of Bowen's lesion and with a 4 months course of supplementation with a high concentration multistrain probiotic formulation administered orally and by rectal instillation with the purpose to reduce local inflammation and to enhance local mucosal immunity.



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Conclusion:



An MRI performed at the end of the supplementation period evidenced the clearance of the anal condylomas previously described and no evidence of residual lymphadenopathies. Trials are therefore required to confirm this therapeutic possibility and for a better understanding of the mechanisms by which this specific probiotic formulation interacts with local epithelium when administered by the anal route

Bianchi, L

Cavallari, En

Ceccarelli, G

Ciardi, A

D'Ettorre, G

Pierangeli, A

Savinelli, S

Vullo, F

Medicine

English

Introduction: Here we present the case of a 56-year-old human immunodeficiency virus (HIV)-infected man with multiple anal condylomas and positivity for human papilloma virus (HPV) 18 on anal brushing. Biopsies of the anal mucosa led to the diagnosis of Bowen's disease and a subsequent pelvic magnetic resonance imaging (MRI) scan evidenced multiple reactive lymphoadenopathies and large intra-anal condylomas. The patient was treated with a complete excision of Bowen's lesion and with a 4 months course of supplementation with a high concentration multistrain probiotic formulation administered orally and by rectal instillation with the purpose to reduce local inflammation and to enhance local mucosal immunity.
Conclusion: An MRI performed at the end of the supplementation period evidenced the clearance of the anal condylomas previously described and no evidence of residual lymphadenopathies. Trials are therefore required to confirm this therapeutic possibility and for a better understanding of the mechanisms by which this specific probiotic formulation interacts with local epithelium when administered by the anal route

Ceccarelli G

Cavallari EN

Savinelli S

Bianchi L

Pierangeli A

Vullo F

Ciardi A

D'ettorre G

Archivio della ricerca- Università di Roma La Sapienza

Clinical Case Report Medicine®OPENClearance of human papillomavirus related analcondylomas after oral and endorectal multistrainprobiotic supplementation in an HIV positive maleA case reportGiancarlo Ceccarelli, MD, PhD, MSca,∗, Eugenio Nelson Cavallari, MDa, Stefano Savinelli, MDa,Luigi Bianchi, MDa, Alessandra Pierangeli, PhDb, Francesco Vullo, MDc, Antonio Ciardi, MDc,Gabriella D’ettorre, MD, PhDaAbstractIntroduction: Here we present the case of a 56-year-old human immunodeficiency virus (HIV)-infected man with multiple analcondylomas and positivity for human papilloma virus (HPV) 18 on anal brushing. Biopsies of the anal mucosa led to the diagnosis ofBowen’s disease and a subsequent pelvic magnetic resonance imaging (MRI) scan evidencedmultiple reactive lymphoadenopathiesand large intra-anal condylomas. The patient was treated with a complete excision of Bowen’s lesion and with a 4 months course ofsupplementation with a high concentration multistrain probiotic formulation administered orally and by rectal instillation with thepurpose to reduce local inflammation and to enhance local mucosal immunity.Conclusion: An MRI performed at the end of the supplementation period evidenced the clearance of the anal condylomaspreviously described and no evidence of residual lymphadenopathies. Trials are therefore required to confirm this therapeuticpossibility and for a better understanding of the mechanisms by which this specific probiotic formulation interacts with localepithelium when administered by the anal route.Abbreviations: AIN = anal intraepithelial neoplasia, HIV = human immunodeficiency virus, HPV = human papilloma virus, HSV =herpes simplex virus, MR = magnetic resonance, MSM = man who have sex with men.Keywords: Bowen’s disease, condylomas, HIV, HPV, papilloma, probiotics, squamocellular intraepithelial carcinoma1. IntroductionThe human immunodeficiency virus (HIV)-infected populationshows a higher prevalence of human papilloma virus (HPV)infection and higher rates of HPV related dysplastic lesions incomparison to the general population. Recent studies suggest thatthe HIV related immune suppression and the interaction betweenHIV and HPV themselves could be responsible for the increasedrisk of HPV related malignancies in this population.[1–4]Editor: Akhilanand Chaurasia.Competing interests and Funding: None of the authors have any competinginterests in the manuscript. No funding was received for this work.Consent for publication: The patient signed written informed consent andconsent for publication of anonymized data.The authors have no conflicts of interest to disclose.a Department of Public Health and Infectious Diseases, b Department of MolecularMedicine, Laboratory of Virology, c Department of Radiological, Oncological andPathology Sciences, “Sapienza” University of Rome, Italy.∗Correspondence: Giancarlo Ceccarelli, Department of Public Health andInfectious Diseases, “Sapienza” University of Rome, Italy, Viale del Policlinico 155,Rome (e-mail: giancarlo.ceccarelli@uniroma1.it).Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.This is an open access article distributed under the Creative CommonsAttribution License 4.0 (CCBY), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.Medicine (2018) 97:16(e0329)Received: 15 February 2017 / Received in final form: 12 March 2018 / Accepted:15 March 2018http://dx.doi.org/10.1097/MD.00000000000103291Moreover, while HIV-infected individuals almost invariablyshow alterations of the normal composition of the gut microbialflora,[5] evidences from literature highlight that a balancedmicrobiota could exert a role in the clearance of HPV infectionthus preventing the risk of HPV related carcinogenesis.[6] In HIVpositive patients, gut dysbiosis is associated with impairment oflocal immune system [7–9] and in this scenario any correctiveaction may contribute to reduce the persistence of HPV infectionand subsequently to the onset of epithelial dysplasia.The use of high doses of oral multistrain probiotics has beeninvestigated as a promising tool for the treatment of gut dysbiosis andthe restoration of gut mucosal immunity in HIV-infected people.[10]Data about the effects of local rectal enema with probiotics on analHPV disease in HIV-infected individuals are unavailable.2. Case presentationWe present the case of a 56-year-old homosexual man who wasdiagnosed with HIV infection in 1998 and which progressed toAIDS in the same year (CD4 nadir 6cell/mL associated topneumonia due to Pneumocystis jirovecii, cervical Herpes Zoster,and disseminated nontuberculous mycobacterial infection).During the follow-up, the patient continuously showed pooradherence to antiretrovirals and required numerous therapyswitch due to virological failure. His medical records showedother pathologic conditions such as thyroid nodular disease,arterial hypertension, syphilis, recurrent anal warts repeatedlytreated with diathermocoagulation and persistent positivity ofHPV 18 in anal brushing.Figure 1. Histology section of Bowen’s disease lesion.Ceccarelli et al. Medicine (2018) 97:16 MedicineOn May 2016, during the periodic follow-up with highresolution anoscopy (HRA), it was highlighted the presence ofmultiple intra anal condylomas. Bioptic samples of the analmucosa led to the diagnosis of squamocellular intraepithelialcarcinoma (Bowen’s disease, anal intraepithelial neoplasia AIN3)(Fig. 1), with an incomplete excision of the lesion. A pelvic MRIscan evidenced granulation tissue in the location of the recentbiopsy, without radiological evidence of residual pathologicaltissue. The MRI also evidenced multiple condylomas of the analcanal, reactive mesorectal and pelvic lymphadenopathies,reactive lymphnodes along the sigmoidal vessels, and thickeningof the mesorectum (Fig. 2A). At the time of anal Bowen’s diseasediagnosis, the patient was clinically asymptomatic and showed agood immune-virological status with a CD4 count of 818cells/mL(28.27%) and HIV-RNA persistently undetectable since 2014.Given the fact that Bowen’s disease is considered a high gradedysplasia (AIN3) with a low risk of invasion (around 5%), weadopted a conservative approach undergoing a complete excisionof the lesion and, once achieved, proposing to the patient a courseFigure 2. Pelvic MRI scan performed before (A) and after (B) supplementa2of supplementation with a multistrain probiotic with dailyendorectal instillation of 900 billion live bacteria and daily oraladministration of 3 sachets, each containing 450 billion livebacteria (probiotic composition: Lactobacillus plantarum DSM24730, Streptococcus thermophilus DSM 24731, Bifidobacte-rium breve DSM 24732, Lactobacillus paracasei DSM 24733,Lactobacillus delbrueckii subsp, bulgaricus DSM 24734,Lactobacillus acidophilus DSM 24735, Bifidobacterium longumDSM 24736, and Bifidobacterium infantis DSM 24737;commercially available as Vivomixx in Europe, Visbiome inUSA and DeSimone Formulation in Korea), with the aim toreduce local inflammation and to rebalance local microbiota,thus possibly restoring in site mucosal immunity.After 4 months of supplementation, a new pelvic MRI scanevidenced the spot of the previous biopsy but no evidence ofmesorectal, iliac, and pelvic lymphadenopathies. Moreover,clearance of the anal condylomas previously described was noted(Fig. 2B) despite HPV18 DNA was still detectable.Six months later, the patient underwent a new HRA thatshowed no evidence of condyloma.3. DiscussionThis case report suggests a potential role for this specific probioticformulation in promoting the regression of anal HPV relatedlesions in HIV-infected individuals. The effects of a number oforal probiotic formulation on HPV associated alterations havebeen mainly studied in the female genital tract; in a prospectivecontrolled pilot study, women with HPV associated low-gradesquamous intraepithelial lesions were randomized for probioticsupplementation: the treated group showed a higher chance ofclearing HPV infection (29% vs 19%, P= .41) and higher rates ofclearance of HPV associated cytological abnormalities (60% vs31%; P= .05) in comparison to the control group.[11] Otherevidences show that a reduced amount of Lactobacillus spp.combined with an increased diversity of the vaginal microbiotacould be involved in HPV acquisition and persistence and in thedevelopment of dysplastic cervical lesions[12,13]; moreover, invitro studies demonstrated a direct cytotoxic effect of certaintion with rectal and oral probiotics. MRI=magnetic resonance imaging.Ceccarelli et al. Medicine (2018) 97:16 www.md-journal.comvaginal microbial strains on HPV-infected cells and an inhibitionof the expression of HPV E6 and E7 oncogenes, which mayprevent malignant transformation in individuals harboring high-risk HPV genotypes.[14–16]Based on the findings of the mentioned gynecological studies,in which the prescription of probiotic supplementation seemsrelated with the regression of HPV related female genital tractlesions, its our opinion that probiotics could also exerted atherapeutic role in our patient. In fact, despite at the momentthere are no similar direct evidences for anal condylomatosis, webelieve that the effects of probiotic strains (described for femalegenital tract) are also possible in the anal district, as observed inthis case.Moreover in HIV positive patients, dysbiosis of the gutmicrobiota largely contributes to the impairment of mucosalimmunity and could facilitate HPV persistence and the subse-quent epithelial transformation. Given that spontaneous regres-sion of multiple large condylomas, such as those observed in ourpatient, is not frequently seen among HIV-infected patients, wehypothesize a beneficial role exerted by this specific probioticformulation in the clearance of HPV related lesions.Finally, data on the effects of probiotic rectal enema on analHPV infection in HIV positive males are lacking. Given theextremely distal localization of the HPV related lesions of ourpatient, we decided to use, together with oral administration,rectal enemas of probiotics to maximize the amount of bacterialcells that would reach the anal canal to effectively interact withthe local epithelium.4. ConclusionsGrowing evidences show the potential beneficial effect ofprobiotics on HPV related disease, also in anal district. Inparticular, in HIV-infected individuals, due to the impairment ofthe immune response and the loss of gut intraepitheliallymphocytes, lower rates of HPV clearance are observed andconsequently spontaneous resolution of multiple large analcondylomas is rare among this population. For this reason, thepositive results of our preliminary experience support thehypothesis of a direct efficacy of oral and rectal multistrainprobiotic administration in the treatment of anal condylomatosisin HIV-infected patients.Author contributionsConceptualization: Giancarlo Ceccarelli, Gabriella d’Ettorre.Data curation: Giancarlo Ceccarelli, Stefano Savinelli, LuigiBianchi, Alessandra Pierangeli, Francesco Vullo, AntonioCiardi, Gabriella d’Ettorre.Formal analysis: Francesco Vullo.Investigation: Stefano Savinelli, Luigi Bianchi, AlessandraPierangeli, Francesco Vullo.Methodology: Giancarlo Ceccarelli, Alessandra Pierangeli.3Resources: Stefano Savinelli, Alessandra Pierangeli.Supervision: Antonio Ciardi, Gabriella d’Ettorre.Validation: Alessandra Pierangeli, Gabriella d’Ettorre.Visualization: Luigi Bianchi.Writing – original draft: Giancarlo Ceccarelli, Gabriellad’Ettorre.Writing – review & editing: Giancarlo Ceccarelli, EugenioNelson Cavallari, Antonio Ciardi.References[1] Denny LA, Franceschi S, de Sanjose S, et al. Human papillomavirus,human immunodeficiency virus and immunosuppression. Vaccine2012;30(suppl 5):F168–74.[2] Palefsky JM, Holly EA, Efirdc JT, et al. Anal intraepithelial neoplasia inthe highly active antiretroviral therapy era amongHIV-positive men whohave sex with men. AIDS 2005;19:1407–14.[3] Mooij SH, van Santen DK, Geskus RB, et al. The effect of HIV infectionon anal and penile human papillomavirus incidence and clearance: acohort study among MSM. AIDS 2016;30:121–32.[4] Geskus RB, Gonzalez C, Torres M, et al. Incidence and clearance of analhigh-risk human papillomavirus in HIV-positive men who have sex withmen: estimates and risk factors. AIDS 2016;30:37–44.[5] Zevin AS, McKinnon L, Burgener A, et al. Microbial translocation andmicrobiome dysbiosis in HIV-associated immune activation. Curr OpinHIV AIDS 2016;11:182–90.[6] Serrano-Villar S, Vásquez-Domínguez E, Pérez-Molina JA, et al. HIV,HPV, and microbiota: partners in crime? AIDS 2017;31:591–4.[7] Vujkovic-Cvijin I, Dunham RM, Iwai S, et al. Dysbiosis of the gutmicrobiota is associated with HIV disease progression and tryptophancatabolism. Sci Transl Med 2013;5: 193ra91.[8] Dillon SM, Lee EJ, Kotter CV, et al. An altered intestinal mucosalmicrobiome in HIV-1 infection is associated with mucosal and systemicimmune activation and endotoxemia. Mucosal Immunol 2014;7:983–94.[9] Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is acause of systemic immune activation in chronic HIV infection. Nat Med2006;12:1365–71.[10] D’Ettorre G, Rossi G, Scagnolari C, et al. Probiotic supplementationpromotes a reduction in T-cell activation, an increase in Th17frequencies, and a recovery of intestinal epithelium integrity andmitochondrial morphology in ART-treated HIV-1-positive patients.Immun Inflam Dis 2017;5:244–60.[11] Verhoeven V, Renard N, Makar A, et al. Probiotics enhance theclearance of human papillomavirus-related cervical lesions: a prospectivecontrolled pilot study. Eur J Cancer Prev 2013;22:46–51.[12] Mitra A, MacIntyre DA, Lee YS, et al. Cervical intraepithelial neoplasiadisease progression is associated with increased vaginal microbiomediversity. Sci Rep 2015;5:16865.[13] Motevaseli E, ShirzadM, Akrami SM, et al. Normal and tumour cervicalcells respond differently to vaginal lactobacilli, independent of pH andlactate. J Med Microbiol 2013;62(pt 7):1065–72.[14] Cha MK, Lee DK, An HM, et al. Antiviral activity of Bifidobacteriumadolescentis SPM1005-A on human papillomavirus type 16. BMC Med2012;10:72.[15] Piyathilake CJ, Ollberding NJ, Kumar R, et al. Cervical microbiotaassociated with higher grade cervical intraepithelial neoplasia in womeninfected with high-risk human papillomaviruses. Cancer Prev Res (Phila)2016;9:357–66.[16] Motevaseli E, Azam R, Akrami SM, et al. The effect of Lactobacilluscrispatus and Lactobacillus rhamnosus culture supernatants on expres-sion of autophagy genes and HPV E6 and E7 oncogenes in the HeLa cellline. Cell J (Yakhteh) 2016;17:601–7.

Clearance of human papillomavirus related anal condylomas after oral and endorectal multistrain probiotic supplementation in an HIV positive male: a case report.

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Clearance of human papillomavirus related anal condylomas after oral and endorectal multistrain probiotic supplementation in an HIV positive male: A case report.

Clearance of human papillomavirus related anal condylomas after oral and endorectal multistrain probiotic supplementation in an HIV positive male: A case report.

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