{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:39:23Z","timestamp":1791920363339,"version":"4.3.4"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2023,8,12]],"date-time":"2023-08-12T00:00:00Z","timestamp":1691798400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,8,12]],"date-time":"2023-08-12T00:00:00Z","timestamp":1691798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007102","name":"Zagazig University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007102","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Dermatol Res"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Treatment of anogenital warts (AGWs) is challenging. Candida antigen immunotherapy has been proven to be a safe and relatively effective therapeutic modality; nevertheless, some patients may experience a partial or no response. Combining Candida antigen with other immunotherapies has been proposed to improve the cure rate. Immunotherapy with human papillomavirus (HPV) vaccines has been tried with conflicting outcomes. This study aimed\u00a0to\u00a0 assess the efficacy and safety of intralesional Candida antigen, either alone or in combination with intralesional bivalent or quadrivalent HPV vaccines, for treating multiple AGWs. Eighty patients with multiple AGWs were included and randomly assigned to four equal groups: group A treated with intralesional Candida antigen only; group B treated with intralesional bivalent HPV vaccine (Cervarix) and Candida; group C treated with intralesional quadrivalent HPV vaccine (Gardasil) and Candida; and group D (control) treated with intralesional saline. Complete clearance of lesions was detected in 40%, 20%, and 60% of patients in Candida monotherapy, Cervarix\/Candida, and Gardasil\/Candida groups, respectively, whereas 40%, 60%, and 20% of patients in the three groups, respectively, showed partial response. Only 10% of the control group had a partial response. Therapeutic outcomes were significantly better in the three treatment groups compared to the control group, with no statistically significant difference between the Candida monotherapy group and the combination groups, but the response was significantly better in the Gardasil\/Candida group than in the Cervarix\/Candida group. No statistically significant difference was found between the studied groups regarding the development of side effects. Moreover, no recurrence was detected in any of the groups throughout the 3-month follow-up period. \u00a0Based on our results,\u00a0combining intralesional HPV vaccines with Candida antigen immunotherapy may have\u00a0no significant benefit for treating multiple AGWs. Candida antigen may be recommended as a relatively effective and inexpensive therapeutic modality. The combination of Gardasil and Candida was also effective but very expensive. The results of the Cervarix\/Candida combination were unsatisfactory. \u00a0This clinical trial was registered and approved prospectively by the ethical review board at Faculty of Medicine, Zagazig University.<\/jats:p>","DOI":"10.1007\/s00403-023-02698-z","type":"journal-article","created":{"date-parts":[[2023,8,12]],"date-time":"2023-08-12T16:01:56Z","timestamp":1691856116000},"page":"2813-2823","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Intralesional bivalent and quadrivalent human papillomavirus vaccines didn\u2019t significantly enhance the response of multiple anogenital warts when co-administered with intralesional Candida antigen immunotherapy. A randomized controlled trial"],"prefix":"10.1007","volume":"315","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5490-9672","authenticated-orcid":false,"given":"Manal","family":"Fawzy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman","family":"Nofal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naglaa","family":"Abdelkhalek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana","family":"Ehab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,8,12]]},"reference":[{"issue":"Suppl 3","key":"2698_CR1","doi-asserted-by":"publisher","first-page":"S143","DOI":"10.1093\/cid\/cir703","volume":"53","author":"EF Dunne","year":"2011","unstructured":"Dunne EF, Friedman A, Datta SD, Markowitz LE, Workowski KA (2011) Updates on human papillomavirus and genital warts and counseling messages from the 2010 sexually transmitted diseases treatment guidelines. Clin Infect Dis 53(Suppl 3):S143\u2013S152. https:\/\/doi.org\/10.1093\/cid\/cir703","journal-title":"Clin Infect Dis"},{"issue":"8","key":"2698_CR2","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1002\/jmv.22111","volume":"83","author":"SL Ball","year":"2011","unstructured":"Ball SL, Winder DM, Vaughan K, Hanna N, Levy J, Sterling JC, Stanley MA, Goon PKC (2011) Analyses of human papillomavirus genotypes and viral loads in anogenital warts. J Med Virol 83(8):1345\u20131350. https:\/\/doi.org\/10.1002\/jmv.22111","journal-title":"J Med Virol"},{"issue":"3","key":"2698_CR3","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1111\/dth.12352","volume":"29","author":"AS Aldahan","year":"2016","unstructured":"Aldahan AS, Mlacker S, Shah VV, Kamath P, Alsaidan M, Samarkandy S, Nouri K (2016) Efficacy of intralesional immunotherapy for the treatment of warts: a review of the literature. Dermatol Ther 29(3):197\u2013207. https:\/\/doi.org\/10.1111\/dth.12352","journal-title":"Dermatol Ther"},{"issue":"5","key":"2698_CR4","doi-asserted-by":"publisher","first-page":"364","DOI":"10.4103\/2229-5178.190487","volume":"7","author":"DM Thappa","year":"2016","unstructured":"Thappa DM, Chiramel MJ (2016) Evolving role of immunotherapy in the treatment of refractory warts. Indian Dermatol Online J 7(5):364\u2013370. https:\/\/doi.org\/10.4103\/2229-5178.190487","journal-title":"Indian Dermatol Online J"},{"issue":"6","key":"2698_CR5","doi-asserted-by":"publisher","first-page":"e15440","DOI":"10.1111\/dth.15440","volume":"35","author":"A Nofal","year":"2022","unstructured":"Nofal A, Adel L, Fawzy M, Elkholy BM (2022) Intralesional immunotherapy for multiple recalcitrant plantar warts: Candida antigen is superior to intralesional purified protein derivative. Dermatol Ther 35(6):e15440. https:\/\/doi.org\/10.1111\/dth.15440","journal-title":"Dermatol Ther"},{"issue":"1","key":"2698_CR6","doi-asserted-by":"publisher","first-page":"21","DOI":"10.15570\/actaapa.2019.5","volume":"28","author":"EH Elmaadawy","year":"2019","unstructured":"Elmaadawy EH, Shams SS, Hegab DS, Zaki RA (2019) Pulsed-dye laser versus intralesional Candida albicans antigen injection in treatment of genital warts. Acta Dermatovenerol Alp Pannonica Adriat 28(1):21\u201326. https:\/\/doi.org\/10.15570\/actaapa.2019.5","journal-title":"Acta Dermatovenerol Alp Pannonica Adriat"},{"issue":"10","key":"2698_CR7","doi-asserted-by":"publisher","first-page":"e15762","DOI":"10.1111\/dth.15762","volume":"35","author":"NZ Tawfik","year":"2022","unstructured":"Tawfik NZ, Eyada MMK, Abdel El Hamid RE, Halim HM (2022) Intralesional injection of purified protein derivative versus Candida antigen in treatment of genital warts. Dermatol Ther 35(10):e15762. https:\/\/doi.org\/10.1111\/dth.15762","journal-title":"Dermatol Ther"},{"issue":"2","key":"2698_CR8","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.jaad.2018.01.011","volume":"79","author":"A Nofal","year":"2018","unstructured":"Nofal A, Khattab F, Nofal E, Elgohary A (2018) Combined acitretin and Candida antigen versus either agent alone in the treatment of recalcitrant warts. J Am Acad Dermatol 79(2):377\u2013378. https:\/\/doi.org\/10.1016\/j.jaad.2018.01.011","journal-title":"J Am Acad Dermatol"},{"issue":"12","key":"2698_CR9","doi-asserted-by":"publisher","first-page":"1606","DOI":"10.1001\/archderm.141.12.1606","volume":"141","author":"M King","year":"2005","unstructured":"King M, Johnson SM, Horn TD (2005) Intralesional immunotherapy for genital warts. Arch Dermatol 141(12):1606\u20131607. https:\/\/doi.org\/10.1001\/archderm.141.12.1606","journal-title":"Arch Dermatol"},{"issue":"3","key":"2698_CR10","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1111\/jocd.13077","volume":"19","author":"A Marei","year":"2020","unstructured":"Marei A, Nofal A, Alakad R, Abdel-Hady A (2020) Combined bivalent human papillomavirus vaccine and Candida antigen versus Candida antigen alone in the treatment of recalcitrant warts. J Cosmet Dermatol 19(3):758\u2013762. https:\/\/doi.org\/10.1111\/jocd.13077","journal-title":"J Cosmet Dermatol"},{"issue":"1","key":"2698_CR11","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1186\/s12874-018-0581-z","volume":"18","author":"ML Murray","year":"2018","unstructured":"Murray ML, Meadows J, Dor\u00e9 CJ, Copas AJ, Haddow LJ, Lacey C et al (2018) Human papillomavirus infection: protocol for a randomised controlled trial of imiquimod cream (5%) versus podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts (HIPvac trial). BMC Med Res Methodol 18(1):125. https:\/\/doi.org\/10.1186\/s12874-018-0581-z","journal-title":"BMC Med Res Methodol"},{"issue":"3","key":"2698_CR12","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1001\/jamadermatol.2013.1463","volume":"149","author":"BS Daniel","year":"2013","unstructured":"Daniel BS, Murrell DF (2013) Complete resolution of chronic multiple verruca vulgaris treated with quadrivalent human papillomavirus vaccine. JAMA Dermatol 149(3):370\u2013372. https:\/\/doi.org\/10.1001\/jamadermatol.2013.1463","journal-title":"JAMA Dermatol"},{"issue":"4","key":"2698_CR13","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.jdcr.2017.05.007","volume":"3","author":"SB Ferguson","year":"2017","unstructured":"Ferguson SB, Gallo ES (2017) Nonavalent human papillomavirus vaccination as a treatment for warts in an immunosuppressed adult. JAAD Case Rep 3(4):367\u2013369. https:\/\/doi.org\/10.1016\/j.jdcr.2017.05.007","journal-title":"JAAD Case Rep"},{"key":"2698_CR14","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.jpeds.2017.11.022","volume":"194","author":"JM Martin","year":"2018","unstructured":"Martin JM, Mateo E, Ram\u00f3n D (2018) Spontaneous regression of a recalcitrant wart after bivalent papillomavirus vaccination. J Pediatr 194:259. https:\/\/doi.org\/10.1016\/j.jpeds.2017.11.022","journal-title":"J Pediatr"},{"issue":"5","key":"2698_CR15","doi-asserted-by":"publisher","first-page":"360","DOI":"10.4103\/0019-5154.117301","volume":"58","author":"I Majid","year":"2013","unstructured":"Majid I, Imran S (2013) Immunotherapy with intralesional Candida albicans antigen in resistant or recurrent warts: a study. Indian J Dermatol 58(5):360\u2013365. https:\/\/doi.org\/10.4103\/0019-5154.117301","journal-title":"Indian J Dermatol"},{"issue":"3","key":"2698_CR16","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1111\/j.1365-2230.1994.tb01167.x","volume":"19","author":"AY Finlay","year":"1994","unstructured":"Finlay AY, Khan GK (1994) Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol 19(3):210\u2013216. https:\/\/doi.org\/10.1111\/j.1365-2230.1994.tb01167.x","journal-title":"Clin Exp Dermatol"},{"key":"2698_CR17","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1111\/ijd.13709","volume":"56","author":"A Nofal","year":"2017","unstructured":"Nofal A, Marei A, Amer A, Amen H (2017) Significance of interferon gamma in the prediction of successful therapy of common warts by intralesional injection of Candida antigen. Int J Dermatol 56:1003\u20131009. https:\/\/doi.org\/10.1111\/ijd.13709","journal-title":"Int J Dermatol"},{"issue":"1","key":"2698_CR18","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/nrmicro1815","volume":"6","author":"MG Netea","year":"2008","unstructured":"Netea MG, Brown GD, Kullberg BJ, Gow NA (2008) An integrated model of the recognition of Candida albicans by the innate immune system. Nat Rev Microbiol 6(1):67\u201378. https:\/\/doi.org\/10.1038\/nrmicro1815","journal-title":"Nat Rev Microbiol"},{"key":"2698_CR19","doi-asserted-by":"publisher","first-page":"1673","DOI":"10.1007\/s42770-020-00322-0","volume":"51","author":"NM Hammad","year":"2020","unstructured":"Hammad NM, Abdelhadi AA, Fawzy MM, Marei A (2020) Complement component 3c and tumor necrosis factor-\u03b1 systemic assessment after Candida antigen immunotherapy in cutaneous warts. Braz J Microbiol 51:1673\u20131681. https:\/\/doi.org\/10.1007\/s42770-020-00322-0","journal-title":"Braz J Microbiol"},{"issue":"47","key":"2698_CR20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3310\/hta24470","volume":"24","author":"R Gilson","year":"2020","unstructured":"Gilson R, Nugent D, Bennett K, Dore CJ, Murray MC, Meadows J et al (2020) Imiquimod versus podophyllotoxin, with and without human papillomavirus vaccine, for anogenital warts: the HIPvac factorial RCT. Health Technol Assess 24(47):1. https:\/\/doi.org\/10.3310\/hta24470","journal-title":"Health Technol Assess"},{"issue":"5","key":"2698_CR21","doi-asserted-by":"publisher","first-page":"e15384","DOI":"10.1111\/dth.15384","volume":"35","author":"E Nofal","year":"2022","unstructured":"Nofal E, Emam S, Aldesoky F, Ghonemy S, Abdelshafy A (2022) Intralesional bivalent human papilloma virus vaccine as a treatment for anogenital warts versus topical podophyllin resin 25%: a pilot study. Dermatol Ther 35(5):e15384. https:\/\/doi.org\/10.1111\/dth.15384","journal-title":"Dermatol Ther"},{"issue":"1","key":"2698_CR22","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.jaad.2019.07.070","volume":"82","author":"A Nofal","year":"2020","unstructured":"Nofal A, Marei A, Ibrahim AM, Nofal E, Nabil M (2020) Intralesional versus intramuscular bivalent human papillomavirus vaccine in the treatment of recalcitrant common warts. J Am Acad Dermatol 82(1):94\u2013100. https:\/\/doi.org\/10.1016\/j.jaad.2019.07.070","journal-title":"J Am Acad Dermatol"},{"issue":"2","key":"2698_CR23","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1590\/s1677-5538.ibju.2018.0355","volume":"45","author":"H Choi","year":"2019","unstructured":"Choi H (2019) Can quadrivalent human papillomavirus prophylactic vaccine be an effective alternative for the therapeutic management of genital warts? An exploratory study. Int Braz J Urol 45(2):361\u2013368. https:\/\/doi.org\/10.1590\/s1677-5538.ibju.2018.0355","journal-title":"Int Braz J Urol"},{"key":"2698_CR24","first-page":"47","volume":"5","author":"AD Protasov","year":"2016","unstructured":"Protasov AD, Lipatov IS, Kostinov MP, Tezikov YV, Shmitko AD, Pakomov DV et al (2016) Anogenital warts: a new way of solving the common problem of urology (results of long-term follow-up). Urologiia 5:47\u201351 (PMID: 28248020)","journal-title":"Urologiia"},{"issue":"5","key":"2698_CR25","doi-asserted-by":"publisher","first-page":"540","DOI":"10.5455\/njppp.2021.11.03083202115032021","volume":"11","author":"S Kumar","year":"2021","unstructured":"Kumar S, Singh O, Brar SK, Gill KS (2021) Efficacy and safety of intralesional quadrivalent human papillomavirus vaccine as immunotherapy in management of recalcitrant genital warts in a tertiary health-care center of North India. Nat J Physiol Pharm Pharmacol 11(5):540\u2013543. https:\/\/doi.org\/10.5455\/njppp.2021.11.03083202115032021","journal-title":"Nat J Physiol Pharm Pharmacol"},{"issue":"12","key":"2698_CR26","doi-asserted-by":"publisher","first-page":"3446","DOI":"10.4161\/hv.34408","volume":"10","author":"DM Herrin","year":"2014","unstructured":"Herrin DM, Coates EE, Costner PJ, Kemp TJ, Nason MC, Saharia KK et al (2014) Comparison of adaptive and innate immune responses induced by licensed vaccines for human papillomavirus. Hum Vaccin Immunother 10(12):3446\u20133454. https:\/\/doi.org\/10.4161\/hv.34408","journal-title":"Hum Vaccin Immunother"},{"issue":"1","key":"2698_CR27","doi-asserted-by":"publisher","first-page":"49","DOI":"10.4103\/2229-3485.106383","volume":"4","author":"U Gupta","year":"2013","unstructured":"Gupta U, Verma M (2013) Placebo in clinical trials. Perspect Clin Res 4(1):49\u201352. https:\/\/doi.org\/10.4103\/2229-3485.106383","journal-title":"Perspect Clin Res"}],"container-title":["Archives of Dermatological Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00403-023-02698-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00403-023-02698-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00403-023-02698-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T07:03:05Z","timestamp":1698649385000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00403-023-02698-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,12]]},"references-count":27,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["2698"],"URL":"https:\/\/doi.org\/10.1007\/s00403-023-02698-z","relation":{},"ISSN":["1432-069X"],"issn-type":[{"value":"1432-069X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,12]]},"assertion":[{"value":"8 June 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 June 2023","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 August 2023","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 August 2023","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest<b>.<\/b>","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study was reviewed and approved by the Institutional Review Board at Faculty of Medicine, Zagazig University (ZU-IRB #9234\/9-1-2022).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"A written informed consent was obtained from all participants included in this study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"All authors accepted the manuscript to be published.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}