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Medicine (Baltimore). 2024 Jun 14; 103(24): e38397.
Published online 2024 Jun 14. doi:10.1097/MD.0000000000038397
PMCID: PMC11175936
PMID: 38875431
Junwu Zhang, MD,
a Jinyao Ni, MD,b Wanzhong Kong, MD,a Jinlin Liu, PhD,c and Yanxia Chen, MDd,*
Author information Article notes Copyright and License information PMC Disclaimer
Abstract
High Immunoglobulin E(IgE) levels associated with hypersensitivity or parasitic infection were well established, but the clinical significance of ultra-low IgE was largely unknown. Previous studies indicated these patients have an elevated risk of cancer, but large-scale epidemiological studies on the prevalence and clinical manifestations of these ultra-low IgE patients are still lacking. A total of 62,997 patients who were admitted to the First Affiliated Hospital of Wenzhou Medical University and had IgE level tests from January 2010 to March 2020 were included. Patients with serum IgE levels < 2 IU/mL were defined to have ultra-low IgE. And the clinical characteristics of these patients were retrospectively analyzed based on electronic medical record system and follow-up. A total of 223 patients (223/62,997, 0.35%) had ultra-low IgE were documented in 62,997 patients who had IgE tests. Among the clinical manifestations of these 223 ultra-low IgE patients, infection ranked first (125/223, 56.05%), following allergic diseases (51/223, 22.87%), hematological disorders (37/223, 16.59%), tumor (27/223, 12.11%) and autoimmune diseases (23/223, 10.31%). To the best of our knowledge, we first reported that the prevalence and clinical characteristics of 223 ultra-low IgE patients in China. The most common comorbidities were infection, allergic diseases, hematological disorders, tumor and autoimmune diseases.
Keywords: China, clinical manifestations, ultra-low IgE
1. Introduction
Immunoglobulin E (IgE) was isolated of human serum in 1968, which was considered to be an immunoglobulin isotype related to allergic reactions.[1] Three soluble isoforms of the IgE Fc receptor are present in human serum, namely high-affinity IgE receptors (FcεRI), low-affinity IgE receptors (FcεRII) and galectin-3. The main function of IgE was a Fc receptor-bound antigen sensor for mast cells and basophils.[2] It was well-recognized that elevated IgE was associated with atopy, allergy and parasitic infestations.[3] The patients with inborn errors of immunity who have significantly increased serum IgE levels and clinical symptoms such as eczema, sinopulmonary and skin infections are often diagnosed with hyper IgE syndrome.[4] However, recent studies have focused on the potential clinical significance of ultra-low serum IgE levels, and serum IgE < 2 IU/mL or IgE < 2.5 IU/mL was defined as IgE deficiency.[5,6] These ultra-low IgE patients also had a higher frequency of autoimmune disease and nonallergic reactive airway disease.[6] Moreover, low serum IgE was a sensitive and specific marker for common variable immunodeficiency patients, and respiratory infections were also frequently documented in these IgE deficiency patients.[7,8] Additionally, other nonspecific manifestations were also observed in these ultra-low IgE patients, e.g. arthralgias and chronic fatigue.[6] All together, these studies indicated that the patients with ultra-low IgE may have great clinical significance. Several retrospective studies investigated the association between the ultra-low IgE levels with malignancy, and found that IgE-deficient patients had a higher frequency and risk of malignancy compared without IgE deficiency individuals.[9,10]
However, large-scale epidemiological studies on the prevalence and clinical manifestations of these ultra-low IgE diseases are still lacking. Moreover, data about these ultra-low IgE patients are also lacking in China. Thus, we design this study to investigate the prevalence and clinical manifestations of ultra-low IgE in a large University hospital in China.
2. Methods
2.1. Patient information
Patients (age > 4) who were had an IgE test in the First Affiliated Hospital of Wenzhou Medical University over a period from January 2010 to March 2020 were included. Finally, 62,997 patients including outpatients, inpatients and healthy population were included in this study according to the database of the Laboratory Information Management System. In 2021, the resident population of Wenzhou district in Zhejiang Province was 9.645 million. And the ultra-low IgE is defined as an IgE level < 2.0 IU/mL.[11] A total of 223 patients of ultra-low IgE patients were screened out on the international criteria of IgE level < 2.0 IU/mL. Among these, 131 patients received Immunoglobulin A (IgA), Immunoglobulin G (IgG), and Immunoglobulin M (IgM) tests (81 patients were normal, 50 patients were abnormal), and 92 patients were not tested. This study was approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University.
2.2. Immunoglobulin Assays
The concentration of serum IgE levels was detected by chemiluminescence and electrochemiluminescence with different types of instruments (Beckman coulter DxI800 and Cobas E602). The concentrations of IgA, IgG and IgM were measured by nephelometry (Beckman Coulter IMMAGE 800 and Siemens BN II), and the laboratory was certificated with ISO15189 standard.
2.3. Statistical analyses
Age is expressed as mean ± standard deviation. Statistical Analyses were performed using the GraphPad Prism 5.
3. Result
3.1. Epidemiology
Among the 62,997 patients who had tested the IgE, 31,592 (50.15%) males and 31,405 (49.85%) females who ranged from 5 to 90 years of age (48.39 ± 19.23 years) were documented. Furthermore, a total of 223 individuals (0.35%) had serum IgE levels < 2.0 IU/mL was found among these 62,997 patients, including 218 adults and 5 children. Of these 223 patients, 89 patients (39.91%) were male and 134 patients (60.09%) were female, the ratio was 1:1.51 (Table (Table11).
Table 1
The basic clinical characteristics of ultra-low IgE patients.
| No. of patients | 223 |
| Adult | 218 |
| Children | 5 |
| Gender | |
| Male | 89 |
| Female | 134 |
| Male/female | 1:1.51 |
| Age (yr) | 48.39 ± 19.23 |
| Prevalence | 0.35% |
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3.2. Infections
To further clarify the clinical characteristics of these ultra-low IgE patients, these patients were retrospectively analyzed based on electronic medical record system and follow-up. Data showed that the infections were the most common comorbidity, while 125/223 patients (56.05%) had various infections. The most common symptoms were pulmonary infection in 43 subjects (19.28%), following bronchitis in 32 subjects (14.35%), pulmonary tuberculosis in 9 subjects (4.04%), and other infection diseases including sinusitis (7 patients, 3.14%), hepatitis B (6 patients, 2.69%), acute upper respiratory tract (4 patients, 1.79%), urinary tract infection (3 patients, 1.35%), laryngotracheitis (3 patients, 1.35%) and other less frequently infections (Table (Table22).
Table 2
The common clinical manifestation of ultra-low IgE.
| N (%) | |
|---|---|
| Infection | 125 (56.05) |
| Pulmonary infection | 43 (19.28) |
| Bronchitis | 32 (14.35) |
| Pulmonary tuberculosis | 9 (4.04) |
| Sinusitis | 7 (3.14) |
| Hepatitis B | 6 (2.69) |
| Acute upper respiratry tract infectin | 4 (1.79) |
| Urinary tract infection | 3 (1.35) |
| Laryngotracheitis | 3 (1.35) |
| Chronic pharyngitis | 2 (0.90) |
| Skin infection | 2 (0.90) |
| Cryptococcal meningitis | 2 (0.90) |
| Pulmonary nocardiosis | 2 (0.90) |
| Fever | 2 (0.90) |
| Prostatitis | 1 (0.45) |
| Herpes zoster | 1 (0.45) |
| Balanoposthitis | 1 (0.45) |
| Otitis media | 1 (0.45) |
| Chronic apical periodontitis | 1 (0.45) |
| Postnasal catarrh | 1 (0.45) |
| Nontuberculous mycobacteria | 1 (0.45) |
| Tuberculosis of knee joint | 1 (0.45) |
| Allergy | 51 (22.87) |
| Allergic dermatitis | 16 (7.17) |
| Urticaria | 9 (4.04) |
| Bronchial asthma | 8 (3.59) |
| Eczema | 6 (2.69) |
| Anaphylactoid purpura | 6 (2.69) |
| Allergic rhinitis | 2 (0.90) |
| Allergic purpura kidney | 2 (0.90) |
| Atopic dermatitis | 1 (0.45) |
| Erythroderma | 1 (0.45) |
| Hemopathy | 37 (16.59) |
| Multiple myeloma | 9 (4.04) |
| Lymphoma | 9 (4.04) |
| Chronic lymphocytic leukemia | 6 (2.69) |
| Acute myelogenous leukemia | 4 (1.79) |
| Aplastic anemia | 3 (1.35) |
| Anemia | 3 (1.35) |
| Myelodysplastic syndromes | 1 (0.45) |
| Granulocytopenia | 1 (0.45) |
| Eosinophilia | 1 (0.45) |
| Tumor | 27 (12.11) |
| Lung cancer | 10 (4.48) |
| Leiomyoma uteri | 5 (2.24) |
| Thymoma | 2 (0.90) |
| Thyroid carcinoma | 2 (0.90) |
| Rectal cancer | 2 (0.90) |
| Endometrial carcinoma | 1 (0.45) |
| Nasopharyngeal carcinoma | 1 (0.45) |
| Esophageal carcinoma | 1 (0.45) |
| Gastric carcinoma | 1 (0.45) |
| Colon cancer | 1 (0.45) |
| Hamartoma of kidney | 1 (0.45) |
| Autoimmune | 23 (10.31) |
| Sjogren syndrome | 4 (1.79) |
| Dermatomyositis | 3 (1.35) |
| Hashimoto thyroiditis | 2 (0.90) |
| Hyperthyroidism | 2 (0.90) |
| Psoriasis | 2 (0.90) |
| ANCA-associated glomerulonephritis | 2 (0.90) |
| ANCA-associated vasculitis | 2 (0.90) |
| Autoimmune hepatitis | 1 (0.45) |
| Rheumatoid arthritis | 1 (0.45) |
| Systemic lupus erythematosus | 1 (0.45) |
| Scleroderma | 1 (0.45) |
| Polymyositis | 1 (0.45) |
| Behcet syndrome | 1 (0.45) |
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Many patients showed more than one clinical feature.
ANCA = Anti-Neutrophil Cytoplasmic Antibodies.
3.3. Allergic diseases
Among these 223 ultra-low IgE patients, 51 patients (22.87%) were associated with atopic manifestations, which included allergic dermatitis (16 patients, 7.17%), urticaria (9 patients, 4.04%), bronchial asthma (8 patients, 3.59%), anaphylactoid purpura (6 patients, 2.69%), eczema (6 patients, 2.69%), allergic rhinitis (2 patients, 0.90%), allergic purpura kidney (2 patients, 0.90%) and atopic dermatitis (1 patient, 0.45%) (Table (Table22).
3.4. Hematological disorders
Moreover, in this cohort, we found that these 223 ultra-low IgE patients were at risk with hematological disorders, which included 28 patients (12.56%) had hematological disorders, including 9 multiple myeloma patients (4.04%), 9 lymphoma patients (4.04%), 6 chronic lymphocytic leukemia patients (2.69%), 4 acute myelogenous leukemia patients (1.79%), aplastic anemia and anemia each in 3 (1.35%) patients (Table (Table22).
3.5. Solid tumor diseases
Recent studies revealed the association between ultra-low serum IgE levels with the risk of malignancy.[3,11] As expected, 27 patients (12.11%) among these 223 ultra-low IgE patients suffered with other solid tumor diseases, including 21 patients with lung cancer (10 patients, 4.48%), thymoma (2 patients, 0.9%), thyroid carcinoma (2 patients, 0.90%), rectal cancer (2 patients,0.9%), endometrial carcinoma (1 patient, 0.45%), nasopharyngeal carcinoma (1 patient, 0.45%), esophageal carcinoma (1 patient, 0.45%), gastric carcinoma (1 patient, 0.45%), and colon cancer (1 patient, 0.45%) (Table (Table22).
3.6. Autoimmune diseases
Additionally, the prevalence of autoimmune disease in these 223 ultra-low IgE patients was 10.31% (n = 23), which included Sjogren syndrome (4 patients,1.79%), dermatomyositis (3 patients, 1.35%), Hashimoto thyroiditis (2 patients, 0.9%), hyperthyroidism (2 patients, 0.9%), psoriasis (2 patients, 0.9%), autoimmune hepatitis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma polymyositis and Behcet syndrome each in 1 patient (0.45%) (Table (Table22).
3.7. Other diseases
Surprisingly, 25 hypertension patients (11.21%) were noted in these 223 ultra-low IgE patients. Chronic renal insufficiency (18 patients, 8.07%) and diabetes (18 patients, 8.07%) were ranked second and third, following chronic obstructive pulmonary disease (11 patients, 4.93%), interstitial lung disease and pulmonary nodules were diagnosed in each 8 patients (3.59%). Bronchiectasis and dermatitis medicamentosa were also documented in 7 patients (3.14%) and 6 patients (2.69%). Interestingly, two patients were diagnosed with rare immunodeficiency of Good’s syndrome (GS) in our study (Table (Table33).
Table 3
Other diseases associated with ultra-low IgE.
| N (%) | |
|---|---|
| Hypertension | 25 (11.21) |
| Chronic renal insufficiency | 18 (8.07) |
| Diabetes | 18 (8.07) |
| Chronic obstructive pulmonary disease | 11 (4.93) |
| Interstitial lung disease | 8 (3.59) |
| Pulmonary nodule | 8 (3.59) |
| Bronchiectasis | 7 (3.14) |
| Dermatitis medicamentosa | 6 (2.69) |
| Thyroid nodule | 4 (1.79) |
| Nephrotic syndrome | 3 (1.35) |
| Pleural effusion | 3 (1.35) |
| Respiratory failure | 3 (1.35) |
| Cardiomyopathies | 3 (1.35) |
| IgA nephropathy | 3 (1.35) |
| Silicosis | 3 (1.35) |
| Airway hyper reactivity | 3 (1.35) |
| Health examination | 2 (0.9) |
| Epilepsy | 2 (0.9) |
| Colonic polyps | 2 (0.9) |
| Good’s syndrome | 2 (0.9) |
| Acne | 2 (0.9) |
| Neurodermatitis | 2 (0.9) |
| Edema of lower extremities | 1 (0.45) |
| Duodenal ulcer | 1 (0.45) |
| Multiple organ failure | 1 (0.45) |
| Vitiligo | 1 (0.45) |
| Chest pain | 1 (0.45) |
| Pulmonary embolism | 1 (0.45) |
| Tremor | 1 (0.45) |
| Erythema nodosum | 1 (0.45) |
| Precocious puberty | 1 (0.45) |
| Xerophthalmia | 1 (0.45) |
| Erythema multiforme | 1 (0.45) |
| Ichthyosis | 1 (0.45) |
| Glomerulonephritis | 1 (0.45) |
| Cardiac insufficiency | 1 (0.45) |
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Many patients showed more than one clinical feature.
4. Discussion
Currently, the prevalence and clinical features of this IgE deficiency were mainly focused on the western countries.[7] The prevalence of ultra-low IgE patients has been reported in 94/4586 (2%) of children in the USA[12] and 74/4013 (1.84%) in the UK.[8] A meta-analysis including several cohorts and other published studies estimated that the prevalence was 3.3% in the general population.[7] However, the prevalence of ultra-low IgE had rarely been reported in Asian countries, and the real prevalence of ultra-low IgE is unclear.[13] Our study showed that the prevalence of ultra-low IgE is 0.35% in a single university hospital. And the resident population of Wenzhou in China was 9.645 million in 2021 which equal to a European country. Compared with other western country studies,[8,12] the prevalence of our result is significantly lower. We hypothesize that the IgE was not routinely examined may result in a lower prevalence than in western countries. Moreover, different diagnosis criteria of IgE deficiency (IgE levels < 2 IU/mL or < 2.5 IU/mL) in these studies may yield different results.
As we know, elevated IgE indicated allergic diseases and total and specific IgE levels of allergens were introduced to diagnose allergic diseases.[14,15] However, the clinical significance of ultra-low IgE with allergic disease was not established. Our study indicated that the association between ultra-low IgE with allergy needs further investigation.
Recently, a number of studies reported that the low IgE level may be a susceptibility marker for malignancy.[10–12] In this study, we also confirmed that the incidence of hematological malignancy was higher than solid tumors. Thus, together with previous studies, this study further confirms that IgE deficiency could play an important role in the pathogenesis of cancer.
Importantly, in this study, we highlight that the most common comorbidity of these IgE deficiency patients were infections, and pulmonary infection ranked first. Thus, our study further supports that IgE deficiency should be consider as an immunodeficiency disease, since several other studies suggested that IgE antibody plays a protective role in humans against bacterial, parasitic, and viral infections.[16,17] Moreover, the low serum IgE was also reported in common variable immunodeficiency (CVID) patients,[7,18] and the CVID was a primary immunodeficiency mainly affects the children. Our results also found two patients of GS, while this disease is a rare secondary immunodeficiency disease which characterized by thymoma with hypogammaglobulinemia. Together, these data supported that these ultra-low IgE patients should considered be an immunodeficiency disease.
Additionally, the study revealed that the ascending of IgE levels may be a risk factor for increased cardiovascular mortality in a cohort of 1496 patients.[19] But a study by Magen et al[20] found a high prevalence of atherosclerotic cardiovascular disease in patients with IgE deficiency, the arterial hypertension and ischemic heart disease had a positive correlation with IgE deficiency. In this study, IgE levels < 2 IU/mL were found in 29 patients with cardiovascular disease which included 25 patients of hypertension, 3 patients of cardiomyopathies and 1 patient of cardiac insufficiency. Thus, the exact role of IgE in cardiovascular disease remains further investigation.
In conclusion, we first described the ultra-low IgE of patient prevalence and clinical manifestations in a large tertiary University hospital in China. The patient with ultra-low IgE can presented with other various diseases, such as infections, allergic diseases, tumors, hematological disorders, autoimmune diseases etc. However, our study had limitations which are a retrospective study design and lack of long-standing follow-up.
Acknowledgments
The authors would like to thank the First Affiliated Hospital of Wenzhou Medical University for their assistance and encouragement.
Author contributions
Conceptualization: Jinlin Liu, Junwu Zhang, Yanxia Chen.
Data curation: Jinyao Ni, Yanxia Chen.
Investigation: Jinyao Ni, Wanzhong Kong.
Methodology: Jinyao Ni, Jinlin Liu.
Writing – original draft: Junwu Zhang.
Writing – review & editing: Jinlin Liu, Yanxia Chen.
Abbreviations:
- CVID
- common variable immunodeficiency
- GS
- Good’s syndrome
- IgA
- immunoglobulin A
- IgE
- immunoglobulin E
- IgG
- immunoglobulin G
- IgM
- immunoglobulin M
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
How to cite this article: Zhang J, Ni J, Kong W, Liu J, Chen Y. Various clinical manifestations of 223 patients with IgE deficiency in a tertiary hospital in China: A cross-sectional study. Medicine 2024;103:24(e38397).
JZ and JN contributed equally to this work.
References
[1] Bennich HH, Ishizaka K, Johansson SGO, Rowe DS, Stanworth DR, Terry WD. Immunoglobulin E, a new class of human immunoglobulin.J Allergy. 1968;42:305–6. [PubMed] [Google Scholar]
[2] Platzer B, Stout M, Fiebiger E. Functions of dendritic-cell-bound IgE in allergy.Mol Immunol. 2015;68(2 Pt A):116–9. [PMC free article] [PubMed] [Google Scholar]
[3] Ferastraoaru D, Bax HJ, Bergmann C, et al.. AllergoOncology: ultra-low IgE, a potential novel biomarker in cancer-a position paper of the European Academy of Allergy and Clinical Immunology (EAACI).Clin Transl Allergy. 2020;10:32. [PMC free article] [PubMed] [Google Scholar]
[4] Gharehzadehshirazi A, Amini A, Rezaei N. Hyper IgE syndromes: a clinical approach.Clin Immunol. 2022;237:108988. [PubMed] [Google Scholar]
[5] Magen E, Schlesinger M, David M, Ben-Zion I, Vardy D. Selective IgE deficiency, immune dysregulation, and autoimmunity.Allergy Asthma Proc. 2014;35:e27–33. [PubMed] [Google Scholar]
[6] Smith JK, Krishnaswamy GH, Dykes R, Reynolds S, Berk SL. Clinical manifestations of IgE hypogammaglobulinemia.Ann Allergy Asthma Immunol. 1997;78:313–8. [PubMed] [Google Scholar]
[7] Lawrence MG, Palacios-Kibler TV, Workman LJ, et al.. Low serum IgE is a sensitive and specific marker for common variable immunodeficiency (CVID).J Clin Immunol. 2018;38:225–33. [PMC free article] [PubMed] [Google Scholar]
[8] McVicker S, Karim MY. IgE deficiency may indicate underlying hypogammaglobulinaemia?J Clin Pathol. 2014;67:832–3. [PubMed] [Google Scholar]
[9] Ferastraoaru D, Gross R, Rosenstreich D. Increased malignancy incidence in IgE deficient patients not due to concomitant common variable immunodeficiency.Ann Allergy Asthma Immunol. 2017;119:267–73. [PubMed] [Google Scholar]
[10] Ferastraoaru D, Rosenstreich D. IgE deficiency and prior diagnosis of malignancy: results of the 2005–2006 National Health and Nutrition Examination Survey.Ann Allergy Asthma Immunol. 2018;121:613–8. [PubMed] [Google Scholar]
[11] Ferastraoaru D, Jordakieva G, Jensen-Jarolim E. The other side of the coin: IgE deficiency, a susceptibility factor for malignancy occurrence.World Allergy Organ J. 2021;14:100505. [PMC free article] [PubMed] [Google Scholar]
[12] Ferastraoaru D, Schwartz D, Rosenstreich D. Increased malignancy rate in children with IgE deficiency: a single-center experience.J Pediatr Hematol Oncol. 2021;43:e472–7. [PubMed] [Google Scholar]
[13] Matricardi PM. The very low IgE producer: allergology, genetics, immunodeficiencies, and oncology.Biomedicines. 2023;11:1378. [PMC free article] [PubMed] [Google Scholar]
[14] Ballardini N, Bergström A, Wahlgren CF, et al.. IgE antibodies in relation to prevalence and multimorbidity of eczema, asthma, and rhinitis from birth to adolescence.Allergy. 2016;71:342–9. [PubMed] [Google Scholar]
[15] Zellweger F, Eggel A. IgE-associated allergic disorders: recent advances in etiology, diagnosis, and treatment.Allergy. 2016;71:1652–61. [PubMed] [Google Scholar]
[16] Duarte J, Deshpande P, Guiyedi V, et al.. Total and functional parasite specific IgE responses in Plasmodium falciparum-infected patients exhibiting different clinical status.Malar J. 2007;6:1. [PMC free article] [PubMed] [Google Scholar]
[17] Pate MB, Smith JK, Chi DS, Krishnaswamy G. Regulation and dysregulation of immunoglobulin E: a molecular and clinical perspective.Clin Mol Allergy. 2010;8:3. [PMC free article] [PubMed] [Google Scholar]
[18] Agondi RC, Barros MT, Kokron CM, et al.. Can patients with common variable immunodeficiency have allergic rhinitis?Am J Rhinol Allergy. 2013;27:79–83. [PubMed] [Google Scholar]
[19] Min KB, Min JY. Risk of cardiovascular mortality in relation to increased total serum IgE levels in older adults: a population-based cohort study.Int J Environ Res Public Health. 2019;16:4350. [PMC free article] [PubMed] [Google Scholar]
[20] Magen E, Mishal J, Vardy D. Selective IgE deficiency and cardiovascular diseases.Allergy Asthma Proc. 2015;36:225–9. [PMC free article] [PubMed] [Google Scholar]
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