Targeting Complex Cutaneous Viral Infections in Search of Inborn Errors of Immunity
DOI:
https://doi.org/10.2340/actadv.v105.41318Keywords:
Papillomaviridae, cutaneous immunity, warts, HPV, inborn errors of immunityAbstract
Inborn errors of immunity are rare diseases and 50–80% present with dermatological manifestations. This study evaluated difficult-to-treat cutaneous human papillomavirus infections and their associations with immunological defects. Patients were recruited from the Dermatological Outpatient Clinic over 2 years. Patients reporting persistent common warts and/or a combination of molluscum contagiosum or more than 2 flat warts, with a clinical assessment of severe or persistent skin infection, met the clinical severity criteria for inclusion. Resistance to several therapies was also considered. A total of 632 patient records were analysed to clinically characterize the warts, laboratory data, treatments used and their responses, comorbidities, and family history. Among these, 459 cases were initially excluded from further evaluation. A questionnaire was provided by phone to 173 patients, among whom 47 patients were selected for an in-person consultation. Of these, 6 met the criteria for further evaluation. Immunological tests revealed neutropenia, low levels of immunoglobulin isotypes (IgA, IgM, and IgG), and reduced frequency of lymphocyte subsets. Family history, flat warts, and associated recurrent viral infections suggested the need for further immunological evaluation. Criteria are proposed for identifying patients with cutaneous warts that warrant additional evaluation for potential inborn errors of immunity.
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Rubin Z, Pappalardo A, Schwartz A, Antoon JW. Prevalence and outcomes of primary immunodeficiency in hospitalized children in the United States. J Allergy Clin Immunol Pract 2018; 6: 1705–1710.e1.
https://doi.org/10.1016/j.jaip.2017.12.002 DOI: https://doi.org/10.1016/j.jaip.2017.12.002
Berron-Ruiz A, Berron-Perez R, Ruiz-Maldonado R. Cutaneous markers of primary immunodeficiency diseases in children. Pediatr Dermatol 2000; 17: 91–96.
https://doi.org/10.1046/j.1525-1470.2000.01721.x DOI: https://doi.org/10.1046/j.1525-1470.2000.01721.x
de Wit J, Brada RJK, van Veldhuizen J, Dalm VASH, Pasmans SGMA. Skin disorders are prominent features in primary immunodeficiency diseases: a systematic overview of current data. Allergy 2019; 74: 464–482.
https://doi.org/10.1111/all.13681 DOI: https://doi.org/10.1111/all.13681
Moin A, Farhoudi A, Moin M, Pourpak Z, Bazargan N. Cutaneous manifestations of primary immunodeficiency diseases in children. Iran J Allergy Asthma Immunol 2006; 5: 121–126.
Béziat V. Human genetic dissection of papillomavirus-driven diseases: new insight into their pathogenesis. Hum Genet 2020; 139: 919–939.
https://doi.org/10.1007/s00439-020-02183-x DOI: https://doi.org/10.1007/s00439-020-02183-x
Al-Herz W, Essa S. Spectrum of viral infections among primary immunodeficient children: report from a national registry. Front Immunol 2019; 10: 1231.
https://doi.org/10.3389/fimmu.2019.01231 DOI: https://doi.org/10.3389/fimmu.2019.01231
Ruffner MA, Sullivan KE, Henrickson SE. Recurrent and sustained viral infections in primary immunodeficiencies. Front Immunol 2017; 8: 665.
https://doi.org/10.3389/fimmu.2017.00665 DOI: https://doi.org/10.3389/fimmu.2017.00665
Dropulic LK, Cohen JI. Severe viral infections and primary immunodeficiencies. Clin Infect Dis 2011; 53: 897–909.
https://doi.org/10.1093/cid/cir610 DOI: https://doi.org/10.1093/cid/cir610
Walter JE, Ballow M. The WHIM syndrome is no longer a whim. J Allergy Clin Immunol Pract 2019; 7: 1578–1579.
https://doi.org/10.1016/j.jaip.2019.03.001 DOI: https://doi.org/10.1016/j.jaip.2019.03.001
de Jong SJ, Imahorn E, Itin P, Uitto J, Orth G, Jouanguy E, et al. Epidermodysplasia verruciformis: inborn errors of immunity to human beta-papillomaviruses. Front Microbiol 2018; 9: 1222.
https://doi.org/10.3389/fmicb.2018.01222 DOI: https://doi.org/10.3389/fmicb.2018.01222
Albert MH, Freeman AF. Wiskott–Aldrich syndrome (WAS) and dedicator of cytokinesis 8- (DOCK8) deficiency. Front Pediatr 2019; 7: 451.
https://doi.org/10.3389/fped.2019.00451 DOI: https://doi.org/10.3389/fped.2019.00451
Marcenaro E, Notarangelo LD, Orange JS, Vivier E. Editorial: NK cell subsets in health and disease: new developments. Front Immunol 2017; 8: 1363.
https://doi.org/10.3389/fimmu.2017.01363 DOI: https://doi.org/10.3389/fimmu.2017.01363
Leto M, Santos Júnior GFD, Porro AM, Tomimori J. Human papillomavirus infection: etiopathogenesis, molecular biology and clinical manifestations. An Bras Dermatol 2011; 86: 306–317.
https://doi.org/10.1590/S0365-05962011000200014 DOI: https://doi.org/10.1590/S0365-05962011000200014
Sterling JC, Handfield-Jones S, Hudson PM, British Association of Dermatologists. Guidelines for the management of cutaneous warts. Br J Dermatol 2001; 144: 4–11.
https://doi.org/10.1046/j.1365-2133.2001.04066.x DOI: https://doi.org/10.1046/j.1365-2133.2001.04066.x
Leiding JW, Holland SM. Warts and all: human papillomavirus in primary immunodeficiencies. J Allergy Clin Immunol 2012; 130: 1030–1048.
https://doi.org/10.1016/j.jaci.2012.07.049 DOI: https://doi.org/10.1016/j.jaci.2012.07.049
Relan M, Lehman HK. Common dermatologic manifestations of primary immune deficiencies. Curr Allergy Asthma Rep 2014; 14: 480.
https://doi.org/10.1007/s11882-014-0480-2 DOI: https://doi.org/10.1007/s11882-014-0480-2
Cagdas D, Ayasun R, Gulseren D, Sanal O, Tezcan I. Cutaneous findings in inborn errors of immunity: an immunologist’s perspective. J Allergy Clin Immunol Pract 2023; 11: 3030–3039.
https://doi.org/10.1016/j.jaip.2023.06.037 DOI: https://doi.org/10.1016/j.jaip.2023.06.037
Shearer WT, Dunn E, Notarangelo LD, Dvorak CC, Puck JM, Logan BR, et al. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J Allergy Clin Immunol 2014; 133: 1092–1098.
https://doi.org/10.1016/j.jaci.2013.09.044 DOI: https://doi.org/10.1016/j.jaci.2013.09.044
Henrickson SE. Susceptibility to papillomavirus. In: Sullivan K, Stiehm RE. Stiehm’s immune deficiencies: inborn errors of immunity. 2nd ed. Amsterdam: Elsevier; 2020: p. 885–993.
https://doi.org/10.1016/B978-0-12-816768-7.00040-5 DOI: https://doi.org/10.1016/B978-0-12-816768-7.00040-5
Subbarayan A, Colarusso G, Hughes SM, Gennery AR, Slatter M, Cant AJ, et al. Clinical features that identify children with primary immunodeficiency diseases. Pediatrics 2011; 127: 810–816.
https://doi.org/10.1542/peds.2010-3680 DOI: https://doi.org/10.1542/peds.2010-3680
Eldeniz FC, Gul Y, Yorulmaz A, Guner SN, Keles S, Reisli I. Evaluation of the 10 warning signs in primary and secondary immunodeficient patients. Front Immunol 2022; 13: 900055.
https://doi.org/10.3389/fimmu.2022.900055 DOI: https://doi.org/10.3389/fimmu.2022.900055
Sharma A, Rajappa M, Saxena A, Sharma M. Cytokine profile in Indian women with cervical intraepithelial neoplasia and cancer cervix. Int J Gynecol Cancer 2007; 17: 879–885. DOI: https://doi.org/10.1111/j.1525-1438.2007.00883.x
https://doi.org/10.1136/ijgc-00009577-200707000-00019 DOI: https://doi.org/10.1136/ijgc-00009577-200707000-00019
Lee BN, Follen M, Shen DY, Malpica A, Adler-Storthz K, Shearer WT, et al. Depressed type 1 cytokine synthesis by superantigen-activated CD4+ T cells of women with human papillomavirus-related high-grade squamous intraepithelial lesions. Clin Diagn Lab Immunol 2004; 11: 239–244.
https://doi.org/10.1128/CDLI.11.2.239-244.2004 DOI: https://doi.org/10.1128/CDLI.11.2.239-244.2004
Trilla-Fuertes L, Gámez-Pozo A, Maurel J, Garcia-Carbonero R, Capdevila J, G-Pastrián L, et al. Description of the genetic variants identified in a cohort of patients diagnosed with localized anal squamous cell carcinoma and treated with panitumumab. Sci Rep 2021; 11: 7402.
https://doi.org/10.1038/s41598-021-86966-w DOI: https://doi.org/10.1038/s41598-021-86966-w
Seale E, Gavigan G. Exacerbation of human papillomavirus infection with initiation of upadacitinib for atopic dermatitis. JAAD Case Rep 2023; 36: 60–62.
https://doi.org/10.1016/j.jdcr.2023.04.019 DOI: https://doi.org/10.1016/j.jdcr.2023.04.019
Kumánovics A, Lee YN, Close DW, Coonrod EM, Ujhazi B, Chen K, et al. Estimated disease incidence of RAG1/2 mutations: a case report and querying the Exome Aggregation Consortium. J Allergy Clin Immunol 2017; 139: 690–692.e3.
https://doi.org/10.1016/j.jaci.2016.07.027 DOI: https://doi.org/10.1016/j.jaci.2016.07.027
Delmonte OM, Villa A, Notarangelo LD. Immune dysregulation in patients with RAG deficiency and other forms of combined immune deficiency. Blood 2020; 135: 610–619.
https://doi.org/10.1182/blood.2019000923 DOI: https://doi.org/10.1182/blood.2019000923
Byun M, Ma CS, Akçay A, Pedergnana V, Palendira U, Myoung J, et al. Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood. J Exp Med 2013; 210: 1743–1759.
https://doi.org/10.1084/jem.20130592 DOI: https://doi.org/10.1084/jem.20130592
Laffort C, Le Deist F, Favre M, Caillat-Zucman S, Radford-Weiss I, Debré M, et al. Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common γc cytokine receptor subunit or JAK-3 deficiency. Lancet 2004; 363: 2051–2054.
https://doi.org/10.1016/S0140-6736(04)16457-X DOI: https://doi.org/10.1016/S0140-6736(04)16457-X
Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2022; 42: 1473–1507.
https://doi.org/10.1007/s10875-022-01289-3 DOI: https://doi.org/10.1007/s10875-022-01289-3
Caka C, Cimen O, Kahyaoğlu P, Tezcan İ, Cagdas D. Selective IgM deficiency: follow-up and outcome. Pediatr Allergy Immunol 2021; 32: 1327–1334.
https://doi.org/10.1111/pai.13497 DOI: https://doi.org/10.1111/pai.13497
Batista CHR, Smanio MCM, Poltronieri PB, Resende LL, Kokron CM, Barros MT, et al. Selective IgM deficiency: evaluation of 75 patients according to different diagnostic criteria. Immunol Res 2024; 73: 15–22.
https://doi.org/10.1007/s12026-024-09568-4 DOI: https://doi.org/10.1007/s12026-024-09568-4
Janssen LMA, Macken T, Creemers MCW, Pruijt JFM, Eijk JJJ, de Vries E. Truly selective primary IgM deficiency is probably very rare. Clin Exp Immunol 2018; 191: 203–211.
https://doi.org/10.1111/cei.13065 DOI: https://doi.org/10.1111/cei.13065
Campochiaro C, Atay S, Clark KEN, Ong V, Denton CP. Autoimmunity and immunodeficiency at the crossroad: autoimmune disorders as the presenting feature of selective IgM deficiency. BMJ Case Rep 2019; 12: e223180.
https://doi.org/10.1136/bcr-2017-223180 DOI: https://doi.org/10.1136/bcr-2017-223180
Platt CD, Zaman F, Bainter W, Stafstrom K, Almutairi A, Reigle M, et al; International Consortium for Immunodeficiencies. Efficacy and economics of targeted panel versus whole-exome sequencing in 878 patients with suspected primary immunodeficiency. J Allergy Clin Immunol 2021; 147: 723–726.
https://doi.org/10.1016/j.jaci.2020.08.022 DOI: https://doi.org/10.1016/j.jaci.2020.08.022
Simon AJ, Golan AC, Lev A, Stauber T, Barel O, Somekh I, et al. Whole exome sequencing (WES) approach for diagnosing primary immunodeficiencies (PIDs) in a highly consanguineous community. Clin Immunol 2020; 214: 108376.
https://doi.org/10.1016/j.clim.2020.108376 DOI: https://doi.org/10.1016/j.clim.2020.108376
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