Overlapping Autoimmunity and Immunodeficiency: A Case of Selective IgA Deficiency with Autoimmune Hemolytic Anemia

Overlapping Autoimmunity and Immunodeficiency: A Case of Selective IgA Deficiency with Autoimmune Hemolytic Anemia | 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 Case Report Overlapping Autoimmunity and Immunodeficiency: A Case of Selective IgA Deficiency with Autoimmune Hemolytic Anemia Laith Khalaf, Mohammad Hamdan, Meera Lahlouh, Kareem Abdul-Haleem This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8348324/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Jan, 2026 Read the published version in BMC Pediatrics → Version 1 posted 11 You are reading this latest preprint version Abstract Background The most common primary immunodeficiency is selective immunoglobulin A deficiency (SIgAD), which is characterized by serum IgA levels equal to or less than 7 mg/dL with normal levels of IgG and IgM in a patient who is at least 4 years old. Most patients are asymptomatic; however, SIgAD increases the risk of respiratory and gastrointestinal infections, autoimmune disorders, transfusion reactions, and atopy. Case Presentation Our 4-year-old female patient had a history of recurrent severe infections requiring multiple hospital admissions, raising our suspicion of an immunodeficiency, especially with a family history of SIgAD. She had several episodes of pallor and jaundice that were caused by autoimmune hemolytic anemia, with the last episode being associated with a severe respiratory infection. Conclusion This case highlights the importance of early diagnosis and ongoing follow-up of children with SIgAD to ensure prompt treatment of infections and autoimmune complications even before the age of four years. It also recommends regular monitoring and early supportive intervention to reduce disease flare-ups and monitor for progression to common variable immunodeficiency. Immunoglobulin A deficiency Immunodeficiency Autoimmune hemolytic anemia Recurrent infection Case report Background Selective immunoglobulin A deficiency (SIgAD) is the most common primary immunodeficiency, affecting males and females equally ( 1 , 2 ). It is defined as serum IgA levels of 7 mg/dL or lower, with normal levels of serum IgG and IgM in a patient aged at least four years, after excluding other causes of immunodeficiency ( 1 – 3 ). Most patients are asymptomatic; however, 20–30% of them develop recurrent severe respiratory and gastrointestinal infections. Other manifestations may include allergies, eczema, asthma, transfusion reactions, and proliferative diseases, with gastrointestinal cancer being the most common proliferative disease ( 1 – 4 ). Autoimmune diseases represent one of the most significant complications of SIgAD, with type 1 diabetes mellitus, thyroid diseases, and inflammatory bowel disease being the most common forms ( 1 , 4 ). Autoimmune hemolytic anemia (AIHA) is another autoimmune disorder that may develop, as in our 4-year-old female patient. Case Presentation At the age of 3 years and 7 months, our patient, born to non-consanguineous parents, with normal development and up-to-date immunizations, presented with a history of recurrent infections and multiple febrile episodes reaching 40˚C. She required repeated hospital admissions and was suspected of having an immunodeficiency, especially with a cousin diagnosed with SIgAD. Her immunoglobulin profile revealed a markedly decreased IgA level of 1 mg/dL (normal range: 22–159 mg/dL), with a normal level of IgM at 106 mg/dL (normal 47–200 mg/dL), while both her IgE and IgG were elevated at 137.7 IU/mL (normal 0.19–16.9 IU/mL) and 2568 mg/dL (normal 441–1135 mg/dL), respectively. These findings supported the diagnosis of SIgAD. No prophylactic antibiotics were prescribed, and she was already up to date on her immunizations. A month later, she had a sudden episode of pallor and jaundice. Her hemoglobin (Hb) level was 5.8 g/dL (normal 10.5–14 g/dL), with a baseline of 10.1 g/dL one month earlier. Mean corpuscular volume was 98.4 fL (normal 70–74 fL), lactate dehydrogenase was 564 U/L (normal 207–414 U/L), total bilirubin was 4.02 mg/dL (normal < 1.2 mg/dL), and direct bilirubin was 1.63 mg/dL (normal < 0.30 mg/dL). She was suspected of having acute hemolytic anemia and was transfused with one unit of packed red blood cells (pRBCs), increasing her Hb level to 9.4 g/dL the next day. A peripheral blood film confirmed acute hemolysis, and an abdominal ultrasound revealed mild hepatosplenomegaly. There was no history of fava bean or drug ingestion, trauma, or recent infection, and no other complaints besides pallor and jaundice. Both direct and indirect Coombs’ tests were positive, confirming the diagnosis of AIHA. She was started on oral prednisolone syrup (2 mg/kg) for three weeks, then was tapered over one week. Flow cytometry revealed normal T-cell count, CD4:CD8 ratio, and natural killer cell count, but an increased B-cell count of 2210 cells/µL (normal 205–1341 cells/µL). Antinuclear antibody was borderline at a 1:80 titer (normal < 80), and double-stranded DNA was equivocal at 28.1 IU/mL (normal < 20 IU/mL). One month after discontinuing prednisolone, she developed another episode of pallor and jaundice, accompanied by a fever of 38°C for one week, vomiting, hypoactivity, and decreased oral intake. Her Hb level was 5.4 g/dL, and she was given an intravenous (IV) shot of methylprednisolone (20 mg), ceftriaxone (75 mg/kg), and transfused with one unit of filtered and irradiated pRBCs, raising her Hb level to 7.0 mg/dL. Although her chest exam was normal, a chest x-ray revealed a right-sided infiltration. She was started on IV ceftriaxone and oral azithromycin, and was discharged two days later on oral ceftriaxone, azithromycin, and prednisolone. Two days after discharge, she presented again with pallor and jaundice, and her Hb level was 6.5 mg/dL. She was started on intravenous immunoglobulins (IVIG, 1 g/kg). Another unit of filtered pRBCs was transfused, and she was started on IV methylprednisolone. Four days later, she was discharged on oral prednisolone (2 mg/kg) as her Hb level gradually improved, reaching 8.2 mg/dL. At the age of 4 years, she developed a productive cough, runny nose, fever up to 38.5°C, and respiratory distress. Chest imaging revealed diffuse bilateral nodular infiltrations with multiple prominent mediastinal and bilateral axillary lymph nodes, accompanied by a mild non-septated bilateral pleural effusion with a thickness of 2.5 cm on the right and 2 cm on the left. Alveolar aspirate tested positive for Epstein-Barr virus, Cytomegalovirus, Varicella-Zoster virus, SARS-CoV-2, and Aspergillus. She was started on IV tazocin, voriconazole, and vancomycin, in addition to oral trimethoprim–sulfamethoxazole and azithromycin. During this episode, her Hb level decreased from 14.7 g/dL before admission to 10.6 g/dL one day after admission. She was started on IVIG (0.5 g/kg) and IV methylprednisolone (1.5 mg/kg). Two weeks later, her Hb level increased to 11.5 g/dL, and she was discharged on oral prednisolone (1.5 mg/kg). Immunoglobulin profile was repeated during this admission and revealed normal levels of IgG, IgE, and IgM, while IgA level was 1 mg/dL, thus confirming the diagnosis of SIgAD. Discussion SIgAD is the most common primary immunodeficiency disorder, defined by a markedly low serum IgA concentration (7 mg/dL or less) with normal levels of both IgG and IgM in individuals over the age of four years ( 5 ). Although many patients remain asymptomatic, this disorder is associated with an increased susceptibility to recurrent respiratory and gastrointestinal infections, as well as a high incidence of allergic and autoimmune diseases. Our patient had a history of recurrent infections, with a severely low IgA concentration (1 mg/dL) and normal IgG and IgE, consistent with the clinical picture of SIgAD. What is striking in this case is the development of AIHA shortly after SIgAD diagnosis. Studies indicate that approximately 20–30% of SIgAD patients exhibit autoimmune manifestations, including immune hematological disorders such as AIHA and immune thrombocytopenia. This association is attributed to impaired immune tolerance mechanisms resulting from a disturbance in the balance between regulatory T lymphocytes and B cells, leading to the abnormal production of autoantibodies. Recent studies have also demonstrated defects in class-switch recombination of B cells in SIgAD patients, contributing to their hyperactivation and the formation of autoantibodies ( 6 ). This is supported by our patient's findings, which showed a marked increase in B-cell counts (2210 cells/µL), indicating uncontrolled immune activation. The recurrence of hemolytic episodes in this case, despite steroid treatment, confirms the presence of persistent immune hyperresponsiveness and raises the possibility that SIgAD represents an initial stage or a limited form of common variable immunodeficiency (CVID) ( 7 ). Several studies have shown that a proportion of patients with SIgAD later develop CVID, a more severe disorder characterized by decreased IgG or IgM levels and a broader impairment of immune function ( 8 ). Therefore, regular monitoring of immunoglobulin levels, study of B-cell subtypes, and assessment of vaccine response are essential to detect this potential transformation early. Another important aspect is the multiple and severe infections the child suffered, including concurrent infections with Epstein-Barr virus, Cytomegalovirus, Varicella-Zoster virus, SARS-CoV-2, and Aspergillus. This pattern of multiple and recurrent infections underscores the impaired mucosal protection in SIgAD, as IgA constitutes the first line of defense at mucosal surfaces by neutralizing and preventing bacterial adhesion ( 9 ). The deficiency of this globulin facilitates the penetration of infectious agents and prolongs their duration, which explains the complex clinical picture in this case. SIgAD can also complicate SARS-CoV-2 infections by contributing to the development of two different autoimmune disorders (type 1 diabetes and Guillain-Barré syndrome) ( 3 ). In terms of treatment, the management of SIgAD focuses on rapid and supportive treatment of infections and avoiding the excessive use of immunosuppressive drugs. There is no specific alternative treatment to replace IgA because IVIG preparations contain trace amounts of it. However, IVIG is an effective treatment option for managing autoimmune complications, such as AIHA, as in this case, which showed a significant improvement in Hb levels after administration ( 10 ). Long-term follow-up is recommended for these patients, including periodic assessment of immunoglobulin levels, screening for potential autoimmune disorders (such as AIHA and thyroid disease) ( 11 ), and family genetic counseling, given the proven genetic predisposition in a proportion of cases. Monitoring the response to prophylactic vaccines and recurrent infections is also recommended as an indicator of disease progression to CVID or the development of a complex immune disorder. Finally, this case highlights the complex interplay between immunodeficiency and autoimmune disease in SIgAD, with the progression of AIHA following diagnosis and the development of severe multiple infections, highlighting the need for close clinical and laboratory follow-up of these patients. It also highlights that SIgAD may not always be a mild or benign disorder as it is thought to be, but can be a precursor to serious immune complications that require careful monitoring and early intervention. Conclusion This case highlights that SIgAD can manifest at an early age, leading to recurrent respiratory and gastrointestinal infections and increasing the risk of developing autoimmune disorders such as AIHA. Therefore, it is essential to suspect the diagnosis even in children younger than four years to initiate early treatment and support, reducing the number and severity of infections and improving quality of life. Regular monitoring of immunoglobulin levels, immune cell profiles, and vaccine response is recommended to detect any progression to CVID and provide timely intervention. Abbreviations SIgAD: selective immunoglobulin A deficiency CVID: common variable immunodeficiency AIHA: autoimmune hemolytic anemia Hb: hemoglobin pRBCs: packed red blood cells US: ultrasound IV: intravenous IVIG: intravenous immunoglobulins Declarations Ethics approval and consent to participate Informed consent was obtained from the patient’s parents for both participation and publication of this report. Consent for publication Informed consent was obtained from the patient’s parents for both participation and publication of this report. Availability of data and materials Not applicable. Competing interests The authors declare that they have no competing interests. Funding This article received no funding. Authors' contributions L.K. contributed to the abstract and case presentation sections. M.H. performed medical proofreading and collected the patient’s data. M.L. contributed to the discussion and conclusion sections and collected the patient’s data. K.A. contributed to the introduction section. All the authors read and approved the final manuscript. Acknowledgments Not applicable. Clinical Trial Number Not applicable. References Killeen RB, Joseph NI. Selective IgA Deficiency. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [cited 2025 Oct 12]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK538205/ Yoshino Y, Kosugi N. Selective IgA Deficiency Complicated with Pernicious Anemia Diagnosed After Febrile Non-Hemolytic Transfusion Reaction. Am J Case Rep 2025 July 9;26:e947678. Pezzutto A, Sirolli V, Di Liberato L, Morroni M, Bonomini M. IgA Deficiency and Membranoproliferative Glomerulonephritis: A Case Report. Int Med Case Rep J 2021 June 3;14:377–80. Hua L, Guo D, Liu X, Jiang J, Wang Q, Wang Y et al. Selective IgA Deficiency with Multiple Autoimmune Comorbidities: A Case Report and Literature Review. Iran J Immunol [Internet]. 2023 May [cited 2025 Oct 17];(Online First). Available from: https://doi.org/10.22034/iji.2023.97452.2513 Yel L. Selective IgA Deficiency. J Clin Immunol. 2010;30(1):10–6. Morawska I, Kurkowska S, Bębnowska D, Hrynkiewicz R, Becht R, Michalski A, et al. The Epidemiology and Clinical Presentations of Atopic Diseases in Selective IgA Deficiency. J Clin Med. 2021;10(17):3809. Bagheri Y, Moeini Shad T, Namazi S, Tofighi Zavareh F, Azizi G, Salami F, et al. B cells and T cells abnormalities in patients with selective IgA deficiency. Allergy Asthma Clin Immunol Off J Can Soc Allergy Clin Immunol. 2023;19(1):23. Odineal DD, Gershwin ME. The Epidemiology and Clinical Manifestations of Autoimmunity in Selective IgA Deficiency. Clin Rev Allergy Immunol. 2020;58(1):107–33. Arslan A, Çokuğraş H, Camcıoğlu Y, Arslan A, Çokuğraş H, Camcıoğlu Y. Demographic Features, Clinical, and Laboratory Findings of Partial and Selective IgA Deficiency in Children. J Pediatr Res [Internet]. 2024 Oct 12 [cited 2025 Oct 24]; Available from: https://jpedres.org/articles/demographic-features-clinical-and-laboratory-findings-of-partial-and-selective-iga-deficiency-in-children/jpr.galenos.2024.89137 Abolhassani H, Gharib B, Shahinpour S, Masoom SN, Havaei A, Mirminachi B, et al. Autoimmunity in patients with selective IgA deficiency. J Investig Allergol Clin Immunol. 2015;25(2):112–9. Aghamohammadi A, Mohammadi J, Parvaneh N, Rezaei N, Moin M, Espanol T, et al. Progression of selective IgA deficiency to common variable immunodeficiency. Int Arch Allergy Immunol. 2008;147(2):87–92. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 30 Jan, 2026 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Revision requested 09 Jan, 2026 Reviews received at journal 22 Dec, 2025 Reviewers agreed at journal 21 Dec, 2025 Reviews received at journal 19 Dec, 2025 Reviewers agreed at journal 18 Dec, 2025 Reviewers agreed at journal 16 Dec, 2025 Reviewers invited by journal 16 Dec, 2025 Editor invited by journal 15 Dec, 2025 Editor assigned by journal 14 Dec, 2025 Submission checks completed at journal 14 Dec, 2025 First submitted to journal 12 Dec, 2025 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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It is defined as serum IgA levels of 7 mg/dL or lower, with normal levels of serum IgG and IgM in a patient aged at least four years, after excluding other causes of immunodeficiency (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Most patients are asymptomatic; however, 20\u0026ndash;30% of them develop recurrent severe respiratory and gastrointestinal infections. Other manifestations may include allergies, eczema, asthma, transfusion reactions, and proliferative diseases, with gastrointestinal cancer being the most common proliferative disease (\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAutoimmune diseases represent one of the most significant complications of SIgAD, with type 1 diabetes mellitus, thyroid diseases, and inflammatory bowel disease being the most common forms (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Autoimmune hemolytic anemia (AIHA) is another autoimmune disorder that may develop, as in our 4-year-old female patient.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eAt the age of 3 years and 7 months, our patient, born to non-consanguineous parents, with normal development and up-to-date immunizations, presented with a history of recurrent infections and multiple febrile episodes reaching 40˚C. She required repeated hospital admissions and was suspected of having an immunodeficiency, especially with a cousin diagnosed with SIgAD.\u003c/p\u003e \u003cp\u003eHer immunoglobulin profile revealed a markedly decreased IgA level of 1 mg/dL (normal range: 22\u0026ndash;159 mg/dL), with a normal level of IgM at 106 mg/dL (normal 47\u0026ndash;200 mg/dL), while both her IgE and IgG were elevated at 137.7 IU/mL (normal 0.19\u0026ndash;16.9 IU/mL) and 2568 mg/dL (normal 441\u0026ndash;1135 mg/dL), respectively. These findings supported the diagnosis of SIgAD. No prophylactic antibiotics were prescribed, and she was already up to date on her immunizations.\u003c/p\u003e \u003cp\u003eA month later, she had a sudden episode of pallor and jaundice. Her hemoglobin (Hb) level was 5.8 g/dL (normal 10.5\u0026ndash;14 g/dL), with a baseline of 10.1 g/dL one month earlier. Mean corpuscular volume was 98.4 fL (normal 70\u0026ndash;74 fL), lactate dehydrogenase was 564 U/L (normal 207\u0026ndash;414 U/L), total bilirubin was 4.02 mg/dL (normal\u0026thinsp;\u0026lt;\u0026thinsp;1.2 mg/dL), and direct bilirubin was 1.63 mg/dL (normal\u0026thinsp;\u0026lt;\u0026thinsp;0.30 mg/dL). She was suspected of having acute hemolytic anemia and was transfused with one unit of packed red blood cells (pRBCs), increasing her Hb level to 9.4 g/dL the next day. A peripheral blood film confirmed acute hemolysis, and an abdominal ultrasound revealed mild hepatosplenomegaly.\u003c/p\u003e \u003cp\u003eThere was no history of fava bean or drug ingestion, trauma, or recent infection, and no other complaints besides pallor and jaundice. Both direct and indirect Coombs\u0026rsquo; tests were positive, confirming the diagnosis of AIHA. She was started on oral prednisolone syrup (2 mg/kg) for three weeks, then was tapered over one week. Flow cytometry revealed normal T-cell count, CD4:CD8 ratio, and natural killer cell count, but an increased B-cell count of 2210 cells/\u0026micro;L (normal 205\u0026ndash;1341 cells/\u0026micro;L). Antinuclear antibody was borderline at a 1:80 titer (normal\u0026thinsp;\u0026lt;\u0026thinsp;80), and double-stranded DNA was equivocal at 28.1 IU/mL (normal\u0026thinsp;\u0026lt;\u0026thinsp;20 IU/mL).\u003c/p\u003e \u003cp\u003eOne month after discontinuing prednisolone, she developed another episode of pallor and jaundice, accompanied by a fever of 38\u0026deg;C for one week, vomiting, hypoactivity, and decreased oral intake. Her Hb level was 5.4 g/dL, and she was given an intravenous (IV) shot of methylprednisolone (20 mg), ceftriaxone (75 mg/kg), and transfused with one unit of filtered and irradiated pRBCs, raising her Hb level to 7.0 mg/dL. Although her chest exam was normal, a chest x-ray revealed a right-sided infiltration. She was started on IV ceftriaxone and oral azithromycin, and was discharged two days later on oral ceftriaxone, azithromycin, and prednisolone.\u003c/p\u003e \u003cp\u003eTwo days after discharge, she presented again with pallor and jaundice, and her Hb level was 6.5 mg/dL. She was started on intravenous immunoglobulins (IVIG, 1 g/kg). Another unit of filtered pRBCs was transfused, and she was started on IV methylprednisolone. Four days later, she was discharged on oral prednisolone (2 mg/kg) as her Hb level gradually improved, reaching 8.2 mg/dL.\u003c/p\u003e \u003cp\u003eAt the age of 4 years, she developed a productive cough, runny nose, fever up to 38.5\u0026deg;C, and respiratory distress. Chest imaging revealed diffuse bilateral nodular infiltrations with multiple prominent mediastinal and bilateral axillary lymph nodes, accompanied by a mild non-septated bilateral pleural effusion with a thickness of 2.5 cm on the right and 2 cm on the left. Alveolar aspirate tested positive for Epstein-Barr virus, Cytomegalovirus, Varicella-Zoster virus, SARS-CoV-2, and Aspergillus. She was started on IV tazocin, voriconazole, and vancomycin, in addition to oral trimethoprim\u0026ndash;sulfamethoxazole and azithromycin.\u003c/p\u003e \u003cp\u003eDuring this episode, her Hb level decreased from 14.7 g/dL before admission to 10.6 g/dL one day after admission. She was started on IVIG (0.5 g/kg) and IV methylprednisolone (1.5 mg/kg). Two weeks later, her Hb level increased to 11.5 g/dL, and she was discharged on oral prednisolone (1.5 mg/kg). Immunoglobulin profile was repeated during this admission and revealed normal levels of IgG, IgE, and IgM, while IgA level was 1 mg/dL, thus confirming the diagnosis of SIgAD.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSIgAD is the most common primary immunodeficiency disorder, defined by a markedly low serum IgA concentration (7 mg/dL or less) with normal levels of both IgG and IgM in individuals over the age of four years (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Although many patients remain asymptomatic, this disorder is associated with an increased susceptibility to recurrent respiratory and gastrointestinal infections, as well as a high incidence of allergic and autoimmune diseases. Our patient had a history of recurrent infections, with a severely low IgA concentration (1 mg/dL) and normal IgG and IgE, consistent with the clinical picture of SIgAD.\u003c/p\u003e \u003cp\u003eWhat is striking in this case is the development of AIHA shortly after SIgAD diagnosis. Studies indicate that approximately 20\u0026ndash;30% of SIgAD patients exhibit autoimmune manifestations, including immune hematological disorders such as AIHA and immune thrombocytopenia. This association is attributed to impaired immune tolerance mechanisms resulting from a disturbance in the balance between regulatory T lymphocytes and B cells, leading to the abnormal production of autoantibodies. Recent studies have also demonstrated defects in class-switch recombination of B cells in SIgAD patients, contributing to their hyperactivation and the formation of autoantibodies (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). This is supported by our patient's findings, which showed a marked increase in B-cell counts (2210 cells/\u0026micro;L), indicating uncontrolled immune activation.\u003c/p\u003e \u003cp\u003eThe recurrence of hemolytic episodes in this case, despite steroid treatment, confirms the presence of persistent immune hyperresponsiveness and raises the possibility that SIgAD represents an initial stage or a limited form of common variable immunodeficiency (CVID) (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Several studies have shown that a proportion of patients with SIgAD later develop CVID, a more severe disorder characterized by decreased IgG or IgM levels and a broader impairment of immune function (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Therefore, regular monitoring of immunoglobulin levels, study of B-cell subtypes, and assessment of vaccine response are essential to detect this potential transformation early.\u003c/p\u003e \u003cp\u003eAnother important aspect is the multiple and severe infections the child suffered, including concurrent infections with Epstein-Barr virus, Cytomegalovirus, Varicella-Zoster virus, SARS-CoV-2, and Aspergillus. This pattern of multiple and recurrent infections underscores the impaired mucosal protection in SIgAD, as IgA constitutes the first line of defense at mucosal surfaces by neutralizing and preventing bacterial adhesion (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The deficiency of this globulin facilitates the penetration of infectious agents and prolongs their duration, which explains the complex clinical picture in this case. SIgAD can also complicate SARS-CoV-2 infections by contributing to the development of two different autoimmune disorders (type 1 diabetes and Guillain-Barr\u0026eacute; syndrome) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn terms of treatment, the management of SIgAD focuses on rapid and supportive treatment of infections and avoiding the excessive use of immunosuppressive drugs. There is no specific alternative treatment to replace IgA because IVIG preparations contain trace amounts of it. However, IVIG is an effective treatment option for managing autoimmune complications, such as AIHA, as in this case, which showed a significant improvement in Hb levels after administration (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eLong-term follow-up is recommended for these patients, including periodic assessment of immunoglobulin levels, screening for potential autoimmune disorders (such as AIHA and thyroid disease) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), and family genetic counseling, given the proven genetic predisposition in a proportion of cases. Monitoring the response to prophylactic vaccines and recurrent infections is also recommended as an indicator of disease progression to CVID or the development of a complex immune disorder.\u003c/p\u003e \u003cp\u003eFinally, this case highlights the complex interplay between immunodeficiency and autoimmune disease in SIgAD, with the progression of AIHA following diagnosis and the development of severe multiple infections, highlighting the need for close clinical and laboratory follow-up of these patients. It also highlights that SIgAD may not always be a mild or benign disorder as it is thought to be, but can be a precursor to serious immune complications that require careful monitoring and early intervention.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case highlights that SIgAD can manifest at an early age, leading to recurrent respiratory and gastrointestinal infections and increasing the risk of developing autoimmune disorders such as AIHA. Therefore, it is essential to suspect the diagnosis even in children younger than four years to initiate early treatment and support, reducing the number and severity of infections and improving quality of life. Regular monitoring of immunoglobulin levels, immune cell profiles, and vaccine response is recommended to detect any progression to CVID and provide timely intervention.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul\u003e\n \u003cli\u003eSIgAD: selective immunoglobulin A deficiency\u003c/li\u003e\n \u003cli\u003eCVID: common variable immunodeficiency\u003c/li\u003e\n \u003cli\u003eAIHA: autoimmune hemolytic anemia\u003c/li\u003e\n \u003cli\u003eHb: hemoglobin\u003c/li\u003e\n \u003cli\u003epRBCs: packed red blood cells\u003c/li\u003e\n \u003cli\u003eUS: ultrasound\u003c/li\u003e\n \u003cli\u003eIV: intravenous\u003c/li\u003e\n \u003cli\u003eIVIG: intravenous immunoglobulins\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from the patient\u0026rsquo;s parents for both participation and publication of this report.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from the patient\u0026rsquo;s parents for both participation and publication of this report.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis article received no funding.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eL.K. contributed to the abstract and case presentation sections.\u003c/p\u003e\n\u003cp\u003eM.H. performed medical proofreading and collected the patient\u0026rsquo;s data.\u003c/p\u003e\n\u003cp\u003eM.L. contributed to the discussion and conclusion sections and collected the patient\u0026rsquo;s data.\u003c/p\u003e\n\u003cp\u003eK.A. contributed to the introduction section.\u003c/p\u003e\n\u003cp\u003eAll the authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eClinical Trial Number\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKilleen RB, Joseph NI. Selective IgA Deficiency. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [cited 2025 Oct 12]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.nih.gov/books/NBK538205/\u003c/span\u003e\u003cspan address=\"http://www.ncbi.nlm.nih.gov/books/NBK538205/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshino Y, Kosugi N. Selective IgA Deficiency Complicated with Pernicious Anemia Diagnosed After Febrile Non-Hemolytic Transfusion Reaction. Am J Case Rep 2025 July 9;26:e947678.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePezzutto A, Sirolli V, Di Liberato L, Morroni M, Bonomini M. IgA Deficiency and Membranoproliferative Glomerulonephritis: A Case Report. Int Med Case Rep J 2021 June 3;14:377\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHua L, Guo D, Liu X, Jiang J, Wang Q, Wang Y et al. Selective IgA Deficiency with Multiple Autoimmune Comorbidities: A Case Report and Literature Review. Iran J Immunol [Internet]. 2023 May [cited 2025 Oct 17];(Online First). Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.22034/iji.2023.97452.2513\u003c/span\u003e\u003cspan address=\"10.22034/iji.2023.97452.2513\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYel L. Selective IgA Deficiency. J Clin Immunol. 2010;30(1):10\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorawska I, Kurkowska S, Bębnowska D, Hrynkiewicz R, Becht R, Michalski A, et al. The Epidemiology and Clinical Presentations of Atopic Diseases in Selective IgA Deficiency. J Clin Med. 2021;10(17):3809.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBagheri Y, Moeini Shad T, Namazi S, Tofighi Zavareh F, Azizi G, Salami F, et al. B cells and T cells abnormalities in patients with selective IgA deficiency. Allergy Asthma Clin Immunol Off J Can Soc Allergy Clin Immunol. 2023;19(1):23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOdineal DD, Gershwin ME. The Epidemiology and Clinical Manifestations of Autoimmunity in Selective IgA Deficiency. Clin Rev Allergy Immunol. 2020;58(1):107\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArslan A, \u0026Ccedil;okuğraş H, Camcıoğlu Y, Arslan A, \u0026Ccedil;okuğraş H, Camcıoğlu Y. Demographic Features, Clinical, and Laboratory Findings of Partial and Selective IgA Deficiency in Children. J Pediatr Res [Internet]. 2024 Oct 12 [cited 2025 Oct 24]; Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://jpedres.org/articles/demographic-features-clinical-and-laboratory-findings-of-partial-and-selective-iga-deficiency-in-children/jpr.galenos.2024.89137\u003c/span\u003e\u003cspan address=\"https://jpedres.org/articles/demographic-features-clinical-and-laboratory-findings-of-partial-and-selective-iga-deficiency-in-children/jpr.galenos.2024.89137\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbolhassani H, Gharib B, Shahinpour S, Masoom SN, Havaei A, Mirminachi B, et al. Autoimmunity in patients with selective IgA deficiency. J Investig Allergol Clin Immunol. 2015;25(2):112\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAghamohammadi A, Mohammadi J, Parvaneh N, Rezaei N, Moin M, Espanol T, et al. Progression of selective IgA deficiency to common variable immunodeficiency. Int Arch Allergy Immunol. 2008;147(2):87\u0026ndash;92.\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":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Immunoglobulin A deficiency, Immunodeficiency, Autoimmune hemolytic anemia, Recurrent infection, Case report","lastPublishedDoi":"10.21203/rs.3.rs-8348324/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8348324/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe most common primary immunodeficiency is selective immunoglobulin A deficiency (SIgAD), which is characterized by serum IgA levels equal to or less than 7 mg/dL with normal levels of IgG and IgM in a patient who is at least 4 years old. Most patients are asymptomatic; however, SIgAD increases the risk of respiratory and gastrointestinal infections, autoimmune disorders, transfusion reactions, and atopy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur 4-year-old female patient had a history of recurrent severe infections requiring multiple hospital admissions, raising our suspicion of an immunodeficiency, especially with a family history of SIgAD. She had several episodes of pallor and jaundice that were caused by autoimmune hemolytic anemia, with the last episode being associated with a severe respiratory infection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case highlights the importance of early diagnosis and ongoing follow-up of children with SIgAD to ensure prompt treatment of infections and autoimmune complications even before the age of four years. It also recommends regular monitoring and early supportive intervention to reduce disease flare-ups and monitor for progression to common variable immunodeficiency.\u003c/p\u003e","manuscriptTitle":"Overlapping Autoimmunity and Immunodeficiency: A Case of Selective IgA Deficiency with Autoimmune Hemolytic Anemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-19 00:10:58","doi":"10.21203/rs.3.rs-8348324/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-09T05:45:19+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-23T01:23:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"70070851177443723600764481832645121046","date":"2025-12-21T13:20:11+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-19T10:51:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"231449211469024115018965378875022334108","date":"2025-12-18T12:17:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"198281157834589269561506266440851318616","date":"2025-12-16T12:39:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-16T12:01:03+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-15T06:32:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-15T02:46:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-15T02:45:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-12-12T18:18:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bb098b58-7420-41b3-a18a-8bb7dda42e4a","owner":[],"postedDate":"December 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-02T16:00:18+00:00","versionOfRecord":{"articleIdentity":"rs-8348324","link":"https://doi.org/10.1186/s12887-026-06570-7","journal":{"identity":"bmc-pediatrics","isVorOnly":false,"title":"BMC Pediatrics"},"publishedOn":"2026-01-30 15:58:03","publishedOnDateReadable":"January 30th, 2026"},"versionCreatedAt":"2025-12-19 00:10:58","video":"","vorDoi":"10.1186/s12887-026-06570-7","vorDoiUrl":"https://doi.org/10.1186/s12887-026-06570-7","workflowStages":[]},"version":"v1","identity":"rs-8348324","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8348324","identity":"rs-8348324","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}