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Low Serum IgE Is a Sensitive and Specific Marker for Common Variable Immunodeficiency (CVID)

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Abstract

Although small prior studies have suggested that IgE can be low in common variable immunodeficiency (CVID), the workup for patients with recurrent infections and suspected hypogammaglobulinemia does not include the routine measurement of serum IgE. We sought to test the hypothesis that low/undetectable serum IgE is characteristic of CVID by comparing the frequency of low/undetectable serum IgE in healthy controls and patients with CVID. We measured total serum IgE in a large multi-center cohort of patients with CVID (n = 354) and compared this to large population-based cohorts of children and adults. We further compared IgE levels in patients with CVID to those with other forms of humoral immunodeficiency, and in a subset, measured levels of allergen-specific serum IgE and IgG subclasses. Lastly, we evaluated for the presence of IgE in commercially available immunoglobulin replacement therapy (IgRT) products. An undetectable serum IgE (< 2 IU/ml) occurs in only 3.3% (95% CI, 1.9–5.7%) of the general population. In contrast, an undetectable IgE occurs in 75.6% (95% CI, 65.6–85.7%) of patients with CVID. Conversely, a high IgE (> 180 IU/ml) is very uncommon in CVID (0.3% of patients). IgE is > 2 IU/ml in 91.2% of patients with secondary hypogammaglobulinemia, and thus, an IgE < LLOD is suggestive of a primary humoral immunodeficiency. Allergen-specific IgE is not detectable in 96.5% of patients with CVID. Sufficient quantities of IgE to change the total serum IgE are not contained in IgRT. The IgG1/IgG4 ratio is increased in subjects with low IgE, regardless of whether they are controls or have CVID. These findings support the routine measurement of serum IgE in the workup of patients with hypogammaglobulinemia.

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Abbreviations

CLIA:

Clinical Laboratory Improvement Amendments

CVID:

Common variable immune deficiency

ELISA:

Enzyme-linked immunosorbent assay

Ig:

Immunoglobulin

IgRT:

Immunoglobulin replacement therapy

IU:

International units

IVIG:

Intravenous immunoglobulin

LLN:

Lower limit of normal

LLOD:

Lower limit of detection

NHANES:

National Health and Nutrition Examination Survey

OLIN:

Obstructive Lung Disease in Northern Sweden

PIDD:

Primary immune deficiency disease

USIDNET:

United States Immunodeficiency Network

UVA:

University of Virginia

XLA:

X-linked agammaglobulinemia

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Acknowledgements

This work was supported by National Institutes of Health grants R56AI120055 (LB), U01AI123337 (LB), AI057438 (LB), AI020565 (TPM), and AI100799 (TPM) as well as the University of Virginia School of Medicine (MGL).

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Authors and Affiliations

  1. Department of Medicine, University of Virginia, Box 801355, Charlottesville, VA, 22908, USA

    Monica G. Lawrence, Thamiris V. Palacios-Kibler, Lisa J. Workman, Alexander J. Schuyler, John W. Steinke, Spencer C. Payne, Emily C. McGowan, Thomas A. E. Platts-Mills & Larry Borish

  2. Department of Otolaryngology, University of Virginia, Charlottesville, VA, USA

    Spencer C. Payne

  3. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Emily C. McGowan

  4. Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA

    James Patrie

  5. Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA

    Ramsay L. Fuleihan

  6. Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Kathleen E. Sullivan

  7. Department of Medicine, Duke University Health System, Durham, NC, USA

    Patricia L. Lugar

  8. Division of Allergy-Immunology, Walter Reed National Military Medical Center, Bethesda, MD, USA

    Camellia L. Hernandez & Douglas E. Beakes

  9. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA

    James W. Verbsky & John M. Routes

  10. Department of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, NY, USA

    Charlotte Cunningham-Rundles

  11. Department of Microbiology, Carter Immunology Center, University of Virginia, Charlottesville, VA, USA

    Larry Borish

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  1. Monica G. Lawrence
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  2. Thamiris V. Palacios-Kibler
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Contributions

Conceptualization, methodology: MGL, SCP, JWS, TAP, LB. Formal analysis: MGL, ECM, JP. Funding acquisition: MGL, LB, TAP. Investigation, resources: MGL, TVP, LJW, AJS, RF, KES, PL, CLH, DEB, JWS, JV, TAP, CCR, JMR, LB. Supervision: TAP, LB, JMR, CCR. Writing and reviewing manuscript: MGL, LB, JMR, CCR, JV, JWS, SCP, TAP.

Corresponding author

Correspondence to Monica G. Lawrence.

Ethics declarations

All human studies were approved by the relevant Institutional Review Board (IRB) (University of Virginia (UVA) IRB 13298, 19688, 18099, and 15596; Children’s Hospital of Wisconsin IRB 99682; Mount Sinai School of Medicine IRB; the regional ethics committee of Umea University; the National Center for Health Statistics IRB). Informed consent was provided by all human subjects.

Conflicts of Interest

John Routes received independent contractor fees from CSL Behring. The rest of the authors declare that they have no relevant conflicts of interest.

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Lawrence, M.G., Palacios-Kibler, T.V., Workman, L.J. et al. Low Serum IgE Is a Sensitive and Specific Marker for Common Variable Immunodeficiency (CVID). J Clin Immunol 38, 225–233 (2018). https://doi.org/10.1007/s10875-018-0476-0

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