Recurrent Visceral Leishmaniasis in a Case with Interleukin-12 Receptor Beta-1 Deficiency

Recurrent Visceral Leishmaniasis in a Case with Interleukin-12 Receptor Beta-1 Deficiency | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Recurrent Visceral Leishmaniasis in a Case with Interleukin-12 Receptor Beta-1 Deficiency hatice uygun, Ayse Ceyda oren, Esra Pekpak Sahinoglu, sinan akbayram This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4187996/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Oct, 2024 Read the published version in Acta Parasitologica → Version 1 posted 5 You are reading this latest preprint version Abstract Purpose In this study, we present the case of a children who was followed up for recurrent visceral leishmaniasis and diagnosed with IL-12Rβ1 deficiency. Methods A female patient who received Bacille Calmette-Guérin (BCG) vaccine 2 months after birth and developed visceral leishmaniasis at the age of 91 months was subsequently diagnosed with IL-12Rβ1 deficiency. The patient's diagnosis and treatment process were examined retrospectively. Results IL-12Rβ1 deficiency is an autosomal recessive disease characterized by susceptibility to recurrent and/or severe infections caused by weakly pathogenic mycobacteria and salmonella. Infections with other intramacrophagic organisms may also occur, although rarely. Based on this information, it is believed that the mutation in the IFN-γ/IL-12 axis in our patient predisposed her to recurrent Leishmania infections. Conclusion This study adds to the limited literature on IL12RB1 deficiency as a cause of VL. Patients diagnosed with VL should be evaluated immunologically, as recurrent Leishmania infections may occur in those with IL-12Rβ1 defects. Children Immun Deficiency Interleukin-12 Receptor Beta-1 Deficiency Visceral Leishmaniasis. Figures Figure 1 Introduction Leishmaniasis is a vector-borne disease complex caused by protozoa of the genus Leishmania and carried by sandflies [ 1 ]. The three main forms of leishmaniasis are Visceral leishmaniasis (VL), Mucocutaneous leishmaniasis (MC), and Cutaneous leishmaniasis (CL) [ 2 ]. In VL, the clinical condition varies from asymptomatic infection to severe disease characterized by fever, pancytopenia, and hepatosplenomegaly, depending on the patient's risk factors [ 3 ]. Leishmaniasis invades and proliferates in host macrophages, evading innate and cell-mediated immune responses [ 4 ]. The control of leishmaniasis relies on the role of interleukin-12 (IL-12) and interferon-gamma (IFN-γ). IL-12 is secreted by dendritic cells and macrophages in response to Leishmania within the macrophage, inducing IFN-γ production. This leads to the death of intramacrophagic pathogens through a series of reactions. Genetic disorders or deficiencies in the IL-12/IFN-γ axis can cause susceptibility to Leishmania infections [ 5 ]. While the frequency of VL increases in cases where the immune system is suppressed, there are few studies showing its relationship with primary deficiencies [ 6 – 10 ]. This study describes a case of IL12RB1 deficiency in a patient with pancytopenia and recurrent VL. Case Presentation The patient was a 91-month-old girl who had received Bacille Calmette-Guérin (BCG) vaccination at 2 months postnatally. In early infancy, the patient experienced BCG-adenitis but did not receive any treatment or diagnosis of immunodeficiency. At 84 months old, the patient started complaining of fever, weakness, and abdominal swelling. Clinical examination revealed hepatosplenomegaly, and blood tests showed pancytopenia. Table 1 provides the results of the examination performed to investigate the etiology of pancytopenia. Bone marrow aspiration was performed, and abundant Leishmania amastigotes were observed in the examination with Giemsa stain (Fig. 1 ). The patient was diagnosed with VL and started treatment with amphotericin B (3–5 mg/kg/day). After 21 days of treatment, the patient's symptoms and laboratory parameters improved. However, VL recurred in August 2023, 5 months after the initial diagnosis. The patient's condition worsened, and conglomerated lymph nodes were observed in the bilateral axilla and neck compartments. The lymph node biopsy confirmed " Leishmaniasis ." Amphotericin B treatment was initiated again. After 15 days of inpatient treatment, the patient's symptoms regressed, laboratory parameters returned to normal, and outpatient treatment was initiated. However, after 3 weeks of outpatient follow-up, the patient developed thrombocytopenia and arthritis in bilateral finger joints and knees. Amphotericin B treatment was administered again. The patient underwent rheumatological evaluation and genetic examination, which revealed a homozygous (99.4%) mutation in the IL12RB1 gene (c.783 + 1G > A p). The patient was started on interferon gamma therapy (50mcgr/m 2 /day/sc) twice a week. After 1 month of follow-up, the patient's blood values increased to normal values. Lymph adenopathies and hepatosplenomegaly are still being monitored, although they are decreasing. Table 1 Laboratory parameters before and after Visceral Leishmaniasis Treatment Laboratory parameters Visceral Leishmaniasis at diagnosis Visceral Leishmaniasis at the time of relapse. Before treatment After treatment Before treatment After treatment White blood cell count (10 3 /uL) 3900 6860 6400 6610 Neutrophil count (10 3 /uL) 830 2890 2040 2170 Platelet Count (10 3 /uL) 48000 193000 82000 173000 Hemoglobin (g/dL) 5.2 9.4 9.3 9.5 Erythrocyte sedimentation rate 127 98 88 66 CRP (mg/dL) 19 2.57 5.85 3 Ferritin (ug/L) 132 46 Folate (ug/L) 9.79 Vitamin B12 (ng/L) 418 Epstein Barr Virus PCR (copy/ml) 0 Cytomegalovirus PCR (copy/ml) 0 Parvo virus PCR (copy/ml) 0 Brucella tube agglutination test (ng/L) Negative CRP : C-reactive protein Discussion VL is a potentially fatal disease if left untreated. The severity of the disease varies depending on factors such as age, immunity, and nutritional status. Symptoms of VL include prolonged fever, weight loss, anemia, hematological changes such as thrombocytopenia and pancytopenia, enlargement of the spleen and liver, and hypergammaglobulinemia [ 11 ]. Microscopic detection of parasitic amastigotes is the classical confirmatory and gold standard test for VL diagnosis [ 12 ]. Protective immunity against Leishmania depends on the interaction between innate and adaptive host immune responses. Monocytes/macrophages and TH1 type CD4 + T lymphocytes play a crucial role in an effective immune response. IL-12 and IFN-γ are important for the development of the TH1 response and macrophage activation [ 13 – 16 ]. Mutations in the IFN-γ/IL-12 axis impair IFN-γ-mediated immunity. In IL-12Rβ1 mutations, a normal cellular response to IFN-γ occurs, but IL-12-dependent production of IFN-γ is abnormal [ 17 ]. Animal studies have shown that IL-12 deficiency plays a significant role in the development of VL [ 16 , 18 ]. However, there are few studies investigating the relationship between leishmaniasis and IL-12 deficiency in humans. Parvaneh et al. described a patient with visceral leishmaniasis and IL-12Rβ1 deficiency, highlighting the importance of IFN-γ immunity in controlling leishmaniasis [ 9 ]. Sanal et al. reported a case of a 5-year-old patient with IL-12Rβ1 deficiency who experienced recurrent VL 6 months apart [ 19 ]. IL-12Rβ1 deficiency is an autosomal recessive disease characterized by susceptibility to recurrent and/or severe infections caused by weakly pathogenic mycobacteria and salmonella. Infections with other intramacrophagic organisms may also occur, although rarely [ 5 , 10 ]. Based on this information, it is believed that the mutation in the IFN-γ/IL-12 axis in our patient predisposed her to recurrent Leishmania infections. In conclusion, this study adds to the limited literature on IL12RB1 deficiency as a cause of VL. Patients diagnosed with VL should be evaluated immunologically, as recurrent Leishmania infections may occur in those with IL-12Rβ1 defects. Declarations Conflict of interest The authors declare no competing interests. Consent to participate Informed consent was obtained from legal guardians to participate. Consent for publication Informed consent was obtained from legal guardians for publication. Authors contributions The authors confirm contribution to the paper as follows: study conception and design: HU, EPS, ACO, SA; data collection: HU, EPS, ACO; analysis and interpretation of results: HU, EPS, SA; draft manuscript preparation: HU, ACO, SA. All authors reviewed the results and approved the final version of the manuscript. Acknowledgments None. References Aronson N, Herwaldt BL, Libman M, Pearson R, Lopez-Velez R, Weina P, Carvalho EM, Ephros M, Jeronimo S, Magill A (2016) Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis 63(12):e202–e264. 10.1093/cid/ciw670 Burza S, Croft SL, Leishmaniasis Boelaert M (2018) Lancet 392(10151):951–970. 10.1016/S0140-6736(18)31204-2 Singh OP, Hasker E, Sacks D, Boelaert M, Sundar S (2014) Asymptomatic Leishmania infection: a new challenge for. Leishmania control 58(10):1424–1429. 10.1093/cid/ciu102 Lammas DA, Casanova JL, Kumararatne DS (2000) Clinical consequences of defects in the IL-12-dependent interferon-gamma (IFN-gamma) pathway. Clin Exp Immunol 121(3):417–425. 10.1046/j.1365-2249.2000.01284.x Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL (2014) Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity. Semin Immunol 26(6):454–470. 10.1016/j.smim.2014.09.008 Pagliano P, Esposito S (2017) Visceral leishmaniosis in immunocompromised host: an update and literature review. J Chemother 29(5):261–266. 10.1080/1120009X.2017.1323150 van Griensven J, Carrillo E, López-Vélez R, Lynen L, Moreno J (2014) Leishmaniasis in immunosuppressed individuals. Clin Microbiol Infect 20(4):286–299. 10.1111/1469-0691.12556 Gonzalez-Granado LI, Dominguez-Pinilla N, Gallego-Bustos F, Ruiz-Contreras J, Allende LM (2016) Visceral Leishmaniasis May Unmask X-linked Hyper-IgM Syndrome. J Clin Immunol 36(4):363–365. 10.1007/s10875-016-0270-9 Parvaneh N, Barlogis V, Alborzi A, Deswarte C, Boisson-Dupuis S, Migaud M, Farnaria C, Markle J, Parvaneh L, Casanova JL, Bustamante J (2017) Visceral leishmaniasis in two patients with IL-12p40 and IL-12Rβ1 deficiencies. Pediatr Blood Cancer 64(6). 10.1002/pbc.26362 Khalid MB, Lemos SG, Myint-Hpu K, Draper D, Stoddard J, Niemela JE, Rosenzweig SD, Pittaluga S, Delmonte OM, Notarangelo LD (2022) IFNγR1 deficiency presenting with visceral leishmaniasis and Mycobacterium Avium infections mimicking HLH. Pediatr Allergy Immunol 33(1):e13653. 10.1111/pai.13653 Murray HW, Brooks EB, DeVecchio JL, Heinzel FP (2003) Immunoenhancement combined with amphotericin B as treatment for experimental visceral leishmaniasis. Antimicrob Agents Chemother 47(8):2513–2517. 10.1128/AAC.47.8.2513-2517.2003 Kumar A, Pandey SC, Samant M (2020) A spotlight on the diagnostic methods of a fatal disease visceral Leishmaniasis. Parasite Immunol 42(10):e12727. 10.1111/pim.12727 Martínez-López M, Soto M, Iborra S, Sancho D (2018) Leishmania hijacks myeloid cells for immune escape. Front Microbiol 9:883. 10.3389/fmicb.2018.00883 Aguilar Torrentera F, Laman JD, Van Meurs M, Adorini L, Muraille E, Carlier Y (2002) Endogenous Interleukin-12 is critical for controlling the late but not the early stage of Leishmania mexicana infection in C57BL/6 mice. Infect Immun 70(9):5075–5080. 10.1128/IAI.70.9.5075-5080.2002 de Souza-Neto SM, Carnerio CM, Vieira LQ, Afonso LCC (2004) Leishmania braziliensis : partial control of experimental infection by interleukin-12 p40 deficient mice. Mem Inst Oswaldo Cruz 99:289–294. 10.1590/s0074-02762004000300009 Murray HW, Tsai CW, Liu J, Ma X (2006) Responses to Leishmania donovani in mice deficient in Interleukin-12 (IL-12), IL-12/IL-23, or IL-18. Infect Immun 74(7):4370–4374. 10.1128/IAI.00422-06 Fieschi C, Bosticardo M, de Beaucoudrey L, Boisson-Dupuis S, Feinberg J, Santos OF, Bustamante J, Levy J, Candotti F, Casanova JL (2004) A novel form of complete IL-12/IL-23 receptor beta1 deficiency with cell surface-expressed nonfunctional receptors. Blood 104(7):2095–2101. 10.1182/blood-2004-02-0584 Murray HW, Berman JD, Davies CR, Saravia NG (2005) Advances in leishmaniasis. Lancet 366(9496):1561–1577. 10.1016/S0140-6736(05)67629-5 Sanal O, Turkkani G, Gumruk F, Yel L, Secmeer G, Tezcan I, Kara A, Ersoy F (2007) A case of interleukin-12 receptor beta-1 deficiency with recurrent leishmaniasis. Pediatr Infect Dis J 26(4):366-8. 10.1097/01. inf. 0000258696.64507.0f Cite Share Download PDF Status: Published Journal Publication published 10 Oct, 2024 Read the published version in Acta Parasitologica → Version 1 posted Editorial decision: Accept 11 Sep, 2024 Reviewers agreed at journal 27 Aug, 2024 Reviewers invited by journal 11 Apr, 2024 Editor assigned by journal 09 Apr, 2024 First submitted to journal 29 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4187996","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":290250797,"identity":"256a335b-0ce9-49a3-886e-694535dd36b0","order_by":0,"name":"hatice uygun","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIiWNgGAWjYFACHgYGxgYGBjYg9RgswMzcQJQWCaAWZmMGBgMgxUikFiCLTRqshYGAFn7+swc/F+6wq+NjP3ysuqDiTzR/O1DLj4ptOLVINpxLlp55JlmCjSct7faMMwa5Mw4zNjD2nLmNU4vBwR4Dad42Zgk2CR6z27xtBrkNQC3MjG14tBzmMf7N21YP1ML/rRikZT5BLcd4zIC2HAbZwsYM0rKBkBbJHh4za96245JtPGnG0jxnjHM3ArUcxOcXfv4zxkAvVPPLtx9++JmnQi533vnDBx/8qMCtBTs4QKL6UTAKRsEoGAVoAADkr04XmSEteAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-8695-9129","institution":"Gaziantep Universitesi Tip Fakultesi","correspondingAuthor":true,"prefix":"","firstName":"hatice","middleName":"","lastName":"uygun","suffix":""},{"id":290250798,"identity":"c71a4188-7abd-4434-8bd4-45f348d5fdd4","order_by":1,"name":"Ayse Ceyda oren","email":"","orcid":"","institution":"Liv Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ayse","middleName":"Ceyda","lastName":"oren","suffix":""},{"id":290250799,"identity":"24bf7f66-60f8-410d-878a-514dffb4a095","order_by":2,"name":"Esra Pekpak Sahinoglu","email":"","orcid":"","institution":"Liv Hospital","correspondingAuthor":false,"prefix":"","firstName":"Esra","middleName":"Pekpak","lastName":"Sahinoglu","suffix":""},{"id":290250800,"identity":"70c9bf8b-d294-445e-bf66-76caaeed4a28","order_by":3,"name":"sinan akbayram","email":"","orcid":"","institution":"Liv Hospital","correspondingAuthor":false,"prefix":"","firstName":"sinan","middleName":"","lastName":"akbayram","suffix":""}],"badges":[],"createdAt":"2024-03-29 12:54:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4187996/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4187996/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11686-024-00926-8","type":"published","date":"2024-10-10T15:56:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":55001314,"identity":"f7d70d35-ee53-4a2f-b15a-19c599c52e24","added_by":"auto","created_at":"2024-04-19 18:37:27","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":84346,"visible":true,"origin":"","legend":"\u003cp\u003eBone marrow aspirate Giemsa stained smear and \u003cem\u003eLeishmania\u003c/em\u003eamastigotes\u003c/p\u003e","description":"","filename":"figure..jpg","url":"https://assets-eu.researchsquare.com/files/rs-4187996/v1/3d93ca7c90967f1f498b43e2.jpg"},{"id":66597032,"identity":"c9d23125-5ba6-46d6-87c6-06ffe7018131","added_by":"auto","created_at":"2024-10-14 16:05:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":408790,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4187996/v1/b09e9e41-eab5-495b-99d7-119955e35cb7.pdf"}],"financialInterests":"","formattedTitle":"Recurrent Visceral Leishmaniasis in a Case with Interleukin-12 Receptor Beta-1 Deficiency","fulltext":[{"header":"Introduction","content":"\u003cp\u003e \u003cem\u003eLeishmaniasis\u003c/em\u003e is a vector-borne disease complex caused by protozoa of the genus \u003cem\u003eLeishmania\u003c/em\u003e and carried by sandflies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The three main forms of \u003cem\u003eleishmaniasis\u003c/em\u003e are Visceral \u003cem\u003eleishmaniasis\u003c/em\u003e (VL), Mucocutaneous \u003cem\u003eleishmaniasis\u003c/em\u003e (MC), and Cutaneous \u003cem\u003eleishmaniasis\u003c/em\u003e (CL) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In VL, the clinical condition varies from asymptomatic infection to severe disease characterized by fever, pancytopenia, and hepatosplenomegaly, depending on the patient's risk factors [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cem\u003eLeishmaniasis\u003c/em\u003e invades and proliferates in host macrophages, evading innate and cell-mediated immune responses [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The control of \u003cem\u003eleishmaniasis\u003c/em\u003e relies on the role of interleukin-12 (IL-12) and interferon-gamma (IFN-γ). IL-12 is secreted by dendritic cells and macrophages in response to \u003cem\u003eLeishmania\u003c/em\u003e within the macrophage, inducing IFN-γ production. This leads to the death of intramacrophagic pathogens through a series of reactions. Genetic disorders or deficiencies in the IL-12/IFN-γ axis can cause susceptibility to \u003cem\u003eLeishmania\u003c/em\u003e infections [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. While the frequency of VL increases in cases where the immune system is suppressed, there are few studies showing its relationship with primary deficiencies [\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study describes a case of IL12RB1 deficiency in a patient with pancytopenia and recurrent VL.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eThe patient was a 91-month-old girl who had received Bacille Calmette-Gu\u0026eacute;rin (BCG) vaccination at 2 months postnatally. In early infancy, the patient experienced BCG-adenitis but did not receive any treatment or diagnosis of immunodeficiency. At 84 months old, the patient started complaining of fever, weakness, and abdominal swelling. Clinical examination revealed hepatosplenomegaly, and blood tests showed pancytopenia. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e provides the results of the examination performed to investigate the etiology of pancytopenia. Bone marrow aspiration was performed, and abundant \u003cem\u003eLeishmania\u003c/em\u003e amastigotes were observed in the examination with Giemsa stain (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The patient was diagnosed with VL and started treatment with amphotericin B (3\u0026ndash;5 mg/kg/day). After 21 days of treatment, the patient's symptoms and laboratory parameters improved. However, VL recurred in August 2023, 5 months after the initial diagnosis. The patient's condition worsened, and conglomerated lymph nodes were observed in the bilateral axilla and neck compartments. The lymph node biopsy confirmed \"\u003cem\u003eLeishmaniasis\u003c/em\u003e.\" Amphotericin B treatment was initiated again. After 15 days of inpatient treatment, the patient's symptoms regressed, laboratory parameters returned to normal, and outpatient treatment was initiated. However, after 3 weeks of outpatient follow-up, the patient developed thrombocytopenia and arthritis in bilateral finger joints and knees. Amphotericin B treatment was administered again. The patient underwent rheumatological evaluation and genetic examination, which revealed a homozygous (99.4%) mutation in the IL12RB1 gene (c.783\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A p). The patient was started on interferon gamma therapy (50mcgr/m\u003csup\u003e2\u003c/sup\u003e/day/sc) twice a week. After 1 month of follow-up, the patient's blood values increased to normal values. Lymph adenopathies and hepatosplenomegaly are still being monitored, although they are decreasing.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLaboratory parameters before and after Visceral \u003cem\u003eLeishmaniasis\u003c/em\u003e Treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLaboratory parameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eVisceral \u003cem\u003eLeishmaniasis\u003c/em\u003e at diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eVisceral \u003cem\u003eLeishmaniasis\u003c/em\u003e at the time of relapse.\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAfter treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBefore treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAfter treatment\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite blood cell count (10\u003csup\u003e3\u003c/sup\u003e/uL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3900\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6860\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6400\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6610\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophil count (10\u003csup\u003e3\u003c/sup\u003e/uL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e830\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2890\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2040\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2170\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet Count (10\u003csup\u003e3\u003c/sup\u003e/uL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e193000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e82000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e173000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eErythrocyte sedimentation rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e127\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerritin (ug/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFolate (ug/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin B12 (ng/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e418\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpstein Barr Virus PCR (copy/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCytomegalovirus PCR (copy/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParvo virus PCR (copy/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrucella tube agglutination test (ng/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCRP\u003c/em\u003e:\u0026nbsp;C-reactive protein\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eVL is a potentially fatal disease if left untreated. The severity of the disease varies depending on factors such as age, immunity, and nutritional status. Symptoms of VL include prolonged fever, weight loss, anemia, hematological changes such as thrombocytopenia and pancytopenia, enlargement of the spleen and liver, and hypergammaglobulinemia [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Microscopic detection of parasitic amastigotes is the classical confirmatory and gold standard test for VL diagnosis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eProtective immunity against \u003cem\u003eLeishmania\u003c/em\u003e depends on the interaction between innate and adaptive host immune responses. Monocytes/macrophages and TH1 type CD4\u0026thinsp;+\u0026thinsp;T lymphocytes play a crucial role in an effective immune response. IL-12 and IFN-γ are important for the development of the TH1 response and macrophage activation [\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Mutations in the IFN-γ/IL-12 axis impair IFN-γ-mediated immunity. In IL-12Rβ1 mutations, a normal cellular response to IFN-γ occurs, but IL-12-dependent production of IFN-γ is abnormal [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnimal studies have shown that IL-12 deficiency plays a significant role in the development of VL [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, there are few studies investigating the relationship between \u003cem\u003eleishmaniasis\u003c/em\u003e and IL-12 deficiency in humans. Parvaneh et al. described a patient with visceral \u003cem\u003eleishmaniasis\u003c/em\u003e and IL-12Rβ1 deficiency, highlighting the importance of IFN-γ immunity in controlling \u003cem\u003eleishmaniasis\u003c/em\u003e [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Sanal et al. reported a case of a 5-year-old patient with IL-12Rβ1 deficiency who experienced recurrent VL 6 months apart [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIL-12Rβ1 deficiency is an autosomal recessive disease characterized by susceptibility to recurrent and/or severe infections caused by weakly pathogenic mycobacteria and salmonella. Infections with other intramacrophagic organisms may also occur, although rarely [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Based on this information, it is believed that the mutation in the IFN-γ/IL-12 axis in our patient predisposed her to recurrent \u003cem\u003eLeishmania\u003c/em\u003e infections.\u003c/p\u003e \u003cp\u003eIn conclusion, this study adds to the limited literature on IL12RB1 deficiency as a cause of VL. Patients diagnosed with VL should be evaluated immunologically, as recurrent \u003cem\u003eLeishmania\u003c/em\u003e infections may occur in those with IL-12Rβ1 defects.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e Informed consent was obtained from legal guardians to participate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e Informed consent was obtained from legal guardians for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm contribution to the paper as follows: study conception and design: HU, EPS, ACO, SA; data collection: HU, EPS, ACO; analysis and interpretation of results: HU, EPS, SA; draft manuscript preparation: HU, ACO, SA. All authors reviewed the results and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAronson N, Herwaldt BL, Libman M, Pearson R, Lopez-Velez R, Weina P, Carvalho EM, Ephros M, Jeronimo S, Magill A (2016) Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). 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Pediatr Infect Dis J 26(4):366-8. 10.1097/01. inf. 0000258696.64507.0f\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"acta-parasitologica","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"actp","sideBox":"Learn more about [Acta Parasitologica](http://link.springer.com/journal/11686)","snPcode":"11686","submissionUrl":"https://submission.springernature.com/new-submission/11686/3","title":"Acta Parasitologica","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Children, Immun Deficiency, Interleukin-12 Receptor Beta-1 Deficiency, Visceral Leishmaniasis.","lastPublishedDoi":"10.21203/rs.3.rs-4187996/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4187996/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003ePurpose\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIn this study, we present the case of a children who was followed up for recurrent visceral leishmaniasis and diagnosed with IL-12Rβ1 deficiency.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA female patient who received Bacille Calmette-Gu\u0026eacute;rin (BCG) vaccine 2 months after birth and developed visceral leishmaniasis at the age of 91 months was subsequently diagnosed with IL-12Rβ1 deficiency. The patient's diagnosis and treatment process were examined retrospectively.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIL-12Rβ1 deficiency is an autosomal recessive disease characterized by susceptibility to recurrent and/or severe infections caused by weakly pathogenic mycobacteria and salmonella. Infections with other intramacrophagic organisms may also occur, although rarely. Based on this information, it is believed that the mutation in the IFN-γ/IL-12 axis in our patient predisposed her to recurrent Leishmania infections.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis study adds to the limited literature on IL12RB1 deficiency as a cause of VL. Patients diagnosed with VL should be evaluated immunologically, as recurrent Leishmania infections may occur in those with IL-12Rβ1 defects.\u003c/p\u003e","manuscriptTitle":"Recurrent Visceral Leishmaniasis in a Case with Interleukin-12 Receptor Beta-1 Deficiency","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-19 18:37:23","doi":"10.21203/rs.3.rs-4187996/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2024-09-11T10:02:04+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-08-27T13:22:01+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-11T19:52:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-09T06:36:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"Acta Parasitologica","date":"2024-03-29T08:54:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"acta-parasitologica","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"actp","sideBox":"Learn more about [Acta Parasitologica](http://link.springer.com/journal/11686)","snPcode":"11686","submissionUrl":"https://submission.springernature.com/new-submission/11686/3","title":"Acta Parasitologica","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f99c7ed2-f732-4307-80e4-c562c98b7887","owner":[],"postedDate":"April 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-14T15:58:51+00:00","versionOfRecord":{"articleIdentity":"rs-4187996","link":"https://doi.org/10.1007/s11686-024-00926-8","journal":{"identity":"acta-parasitologica","isVorOnly":false,"title":"Acta Parasitologica"},"publishedOn":"2024-10-10 15:56:58","publishedOnDateReadable":"October 10th, 2024"},"versionCreatedAt":"2024-04-19 18:37:23","video":"","vorDoi":"10.1007/s11686-024-00926-8","vorDoiUrl":"https://doi.org/10.1007/s11686-024-00926-8","workflowStages":[]},"version":"v1","identity":"rs-4187996","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4187996","identity":"rs-4187996","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}