Overlapping autoimmunity and immunodeficiency: a case of selective IgA deficiency with autoimmune hemolytic anemia

Abstract

Background

The most prevalent 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.

Background

Selective immunoglobulin A deficiency (SIgAD) is the most prevalent form of 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, as she had no other causes of hypogammaglobulinemia, with a free drug history and no chromosomal or genetic disorders. 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 prevalent 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. 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 [5]. 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 like AIHA; however, thyroid disease, type 1 diabetes mellitus, and inflammatory bowel disease are more common. 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), which is a more severe disorder characterized by decreased levels of IgG or IgM and a broader impairment of immune function [7, 8]. A study involving 184 pediatric SIgAD patients reported that 2% of them progressed to CVID, with hematological autoimmunity being a predictor of progression [6, 9]. Multiple theories were suggested to explain the connection between SIgAD and CVID, including single-gene mutations and similar autoantibodies. Progression to CVID could be predicted using human leukocyte antigen typing; however, more studies are needed to determine the cause of this connection [6, 10]. Therefore, regular monitoring of immunoglobulin levels, studying B-cell subtypes, and assessing vaccine response are essential to detect this potential progression 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 [11]. 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 [12].

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) [13], and family genetic counseling, given the proven genetic predisposition in a proportion of cases. Monitoring the response to 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. In Palestine, no polysaccharide antigen nor IgG subclass testing is available, limiting our ability to monitor this case.

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

IV

Intravenous

IVIG

Intravenous immunoglobulins

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.

Funding

This article received no funding.

Data availability

No datasets were generated or analysed during the current study.

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.

Competing interests

The authors declare no competing interests.