Background Inborn Errors of Immunity (IEI), previously termed primary immunodeficiencies, include a wide range of disorders characterized by immune dysregulation, autoimmunity, and susceptibility to infections. Objective This study aims to identify non-infectious warning signs of IEI in children of autoimmune disorders presenting with atypical noninfectious symptoms, facilitating early diagnosis and intervention. Methods This cross-sectional study included 100 children below the age of 18 with different immunological disorders and suspected of having IEI. Twenty-two cases were confirmed using clinical and laboratory evaluations. Data collected included demographic details, clinical examinations, and laboratory investigations such as immunoglobulin levels (IgA, IgM, IgG, IgE), CD markers (CD3, CD4, CD8, CD19, CD56), and specific protein analyses (e.g., DOCK8, LRBA, WAS), using flow cytometry and targeted intracellular protein analysis. Correlation between clinical features and confirmed IEI was assessed using Pearson’s correlation coefficient. Results Among the studied cases, immune thrombocytopenic purpura (ITP) was the most common diagnosis (19%), followed by systemic lupus erythematosus (SLE, 16%), type 1 diabetes mellitus (15%), inflammatory bowel disease (IBD, 13%), and autoimmune hemolytic anemia (8%). From the 100 enrolled patients, 22 (22%) were diagnosed with IEI. The mean age of participants was 9.04 ± 4.4 years, with a male predominance (72.7%) among confirmed IEI cases. Autoimmune lymphoproliferative syndrome (ALPS) was the most frequent IEI disorder (18.2%), followed by DOCK8 deficiency, adenosine deaminase 2 deficiency, and common variable immunodeficiency (each 13.6%). Common presenting complaints included diarrhea (31.8%), recurrent anemia (22.7%), and recurrent fever (18.2%). Hepatosplenomegaly (22.7%) and lymphadenopathy were the most frequent clinical findings. Hepatosplenomegaly (22.7%) was strongly associated with confirmed IEI (r = 0.67, p < 0.001). Other significant correlations included failure to thrive (r = 0.61, p = 0.001), autoimmune cytopenias (r = 0.56, p = 0.005), lymphadenopathy (r = 0.52, p = 0.01), eczema (r = 0.48, p = 0.02), and recurrent fever (r = 0.44, p = 0.03). A wide variation in immunoglobulin levels was observed, including low CD19 and CD56 levels, and normal complement profiles. Elevated IgE levels were observed, and autoimmune hemolysis was evident in confirmed IEI patients. Conclusion This study highlights the importance of recognizing non-infectious manifestations, such as autoimmune cytopenia, atopy, and lymphoproliferation, as potential indicators of IEI, even with the absence of recurrent or severe infections. Early identification of these signs can reduce diagnostic delays and improve outcomes in pediatric patients.

Evaluation of non-infectious warning signs in children with inborn errors of immunity

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2025年8月25日

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Eman Mohamed Fahmy,
Amany Mansour Shalaby,
Eman H. Salama,
Omar Ahmed Abd Ellatif

摘要

Background

Inborn Errors of Immunity (IEI), previously termed primary immunodeficiencies, include a wide range of disorders characterized by immune dysregulation, autoimmunity, and susceptibility to infections.

Objective

This study aims to identify non-infectious warning signs of IEI in children of autoimmune disorders presenting with atypical noninfectious symptoms, facilitating early diagnosis and intervention.

Methods

This cross-sectional study included 100 children below the age of 18 with different immunological disorders and suspected of having IEI. Twenty-two cases were confirmed using clinical and laboratory evaluations. Data collected included demographic details, clinical examinations, and laboratory investigations such as immunoglobulin levels (IgA, IgM, IgG, IgE), CD markers (CD3, CD4, CD8, CD19, CD56), and specific protein analyses (e.g., DOCK8, LRBA, WAS), using flow cytometry and targeted intracellular protein analysis. Correlation between clinical features and confirmed IEI was assessed using Pearson’s correlation coefficient.

Results

Among the studied cases, immune thrombocytopenic purpura (ITP) was the most common diagnosis (19%), followed by systemic lupus erythematosus (SLE, 16%), type 1 diabetes mellitus (15%), inflammatory bowel disease (IBD, 13%), and autoimmune hemolytic anemia (8%). From the 100 enrolled patients, 22 (22%) were diagnosed with IEI. The mean age of participants was 9.04 ± 4.4 years, with a male predominance (72.7%) among confirmed IEI cases. Autoimmune lymphoproliferative syndrome (ALPS) was the most frequent IEI disorder (18.2%), followed by DOCK8 deficiency, adenosine deaminase 2 deficiency, and common variable immunodeficiency (each 13.6%). Common presenting complaints included diarrhea (31.8%), recurrent anemia (22.7%), and recurrent fever (18.2%). Hepatosplenomegaly (22.7%) and lymphadenopathy were the most frequent clinical findings. Hepatosplenomegaly (22.7%) was strongly associated with confirmed IEI (r = 0.67, p < 0.001). Other significant correlations included failure to thrive (r = 0.61, p = 0.001), autoimmune cytopenias (r = 0.56, p = 0.005), lymphadenopathy (r = 0.52, p = 0.01), eczema (r = 0.48, p = 0.02), and recurrent fever (r = 0.44, p = 0.03). A wide variation in immunoglobulin levels was observed, including low CD19 and CD56 levels, and normal complement profiles. Elevated IgE levels were observed, and autoimmune hemolysis was evident in confirmed IEI patients.

Conclusion

This study highlights the importance of recognizing non-infectious manifestations, such as autoimmune cytopenia, atopy, and lymphoproliferation, as potential indicators of IEI, even with the absence of recurrent or severe infections. Early identification of these signs can reduce diagnostic delays and improve outcomes in pediatric patients.