Abstract
Purpose
This study aimed to investigate the correlation between calculated globulin (CG, total protein level minus albumin level) and the gamma globulin fraction (Gamma), obtained from serum protein electrophoresis with serum IgG levels in adults (≥ 18 years).
Methods
Using linear regression models, analyses of CG and Gamma levels correlation with IgG levels in adults were performed. Receiver-operator curves were created to determine cutoff values and the respective sensitivity and specificity measures.
Results
A total of 886 samples were analyzed. CG and Gamma were positively and statistically correlated with IgG levels (r2 = 0.4628 for CG, and = 0.7941 for Gamma, p < 0.0001 for both analyses). For the detection of hypogammaglobulinemia, i.e., IgG level below the reference value (6 g/L), a CG cutoff value of 24 g/L showed a sensitivity of 86.2% (95% CI 69.4–94.5) and a specificity of 92% (90.0–93.6). A Gamma cutoff value of 7.15 g/L yielded a sensitivity of 100% (88.3–100) and a specificity of 96.8 (95.3–97.8).
Conclusion
Both CG and Gamma levels determined by protein electrophoresis analysis may be used to screen for antibody deficiencies in adults, enabling earlier diagnosis of antibody deficiencies in a routine clinical setting.
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Data Availability
All data regarding the findings are available upon request to the corresponding author.
Change history
12 August 2023
A Correction to this paper has been published: https://doi.org/10.1007/s10875-023-01568-7
Abbreviations
- CG:
-
Calculated globulin
- IgG:
-
Immunoglobulin
- Gamma:
-
Gamma globulin
- PAD:
-
Primary antibody deficiency
- PID:
-
Primary immune deficiency
- LFT:
-
Liver function test
- SAD:
-
Secondary antibody deficiency
References
Durandy A, Kracker S, Fischer A. Primary antibody deficiencies. Nat Rev Immunol. 2013;13(7):519–33.
Patel S, Carbone J, Jolles S. The expanding field of secondary antibody deficiency: causes, diagnosis, and management. Front Immunol. 2019;10:33.
Bousfiha A, Moundir A, Tangye SG, Picard C, Jeddane L, Al-Herz, et al. The 2022 Update of IUIS phenotypical classification for human inborn errors of immunity. J Clin Immunol. 2022;42(7):1508–20.
Quinn J, Modell V, Orange JS, Modell F. Growth in diagnosis and treatment of primary immunodeficiency within the global Jeffrey Modell Centers Network. Allergy Asthma Clin Immunol. 2022;18(1):19.
Jolles S. The variable in common variable immunodeficiency: a disease of complex phenotypes. J Allergy Clin Immunol Pract. 2013;1(6):545–56 (quiz 557).
Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, Morena MT, et al. International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. J Allergy Clin Immunol Pract. 2016;4(1):38–59.
Ameratunga R, Allan C, Woon S-T. Defining common variable immunodeficiency disorders in 2020. Immunol Allergy Clin N Am. 2020;40:403–20.
Latin American Society of Immunodeficiencies PID Registry homepage. Available at: https://www.lasidregistryorg/view/statistics. Accessed January 10, 2023.
Seidel GM, Kindle G, Gathmann B, Quinti I, Buckland M, Montfrans J, et al. ESID Registry Working Party and collaborators The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract. 2019;7(6):1763–70.
Cunninghan-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34–48.
Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112:277–86.
Thalhammer J, Kindle G, Nieters A, Rusch S, Seppänen MRJ, Fischer A, et al. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations. J Allergy Clin Immunol. 2021;148(5):1332–41.
Agarwal S, Cunningham-Rundles C. Autoimmunity in common variable immunodeficiency. Ann Allergy Asthma Immunol. 2019;123(5):454–60.
Kiace F, Azizi G, Rafiemanesh H, Zainaldain H, Sadaat RF, Alizadeh M, et al. Malignancy in common variable immunodeficiency: a systematic review and meta-analysis. Expert Rev Clin Immunol. 2019;15(10):1105–13.
Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119:1650–7.
Hovermale E, Scalchunes C, Boyle M. Comparative effectiveness research in the United States and primary immunodeficiency disease. Pharmaceutical policy Law. 2011;13:183–91.
Otani IM, Lehman HK, Jongco AM, Tsao LR, Azar AE, Tarrant TK, et al. Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: a work group report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees. J Allergy Clin Immunol. 2022;149:1525–60.
Dhalla F, Misbah SA. Secondary antibody deficiencies. Curr Opin Allergy Clin Immunol. 2015;15(6):505–13.
Chinen J, Sharer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol. 2010;125(2 suppl):S195-203.
Tallantyre EC, Robertson NP, Jolles S. Secondary antibody deficiency in neurology. Curr Opin Allergy Clin Immunol. 2018;18(6):481–8.
Jolles S, Giralt S, Kerre T, Hillard LM, Mustafa SS, Ris R, Vinh DC. Agents contributing to secondary immunodeficiency development in patients with multiple myeloma, chronic lymphocytic leukemia and non-hodgkin lymphoma: a systematic literature review. Systematic Review Front Oncol. Hematologic Malignancies. In press22
Dhalla F, Lucas M, Schuh A, Bhole M, Jain R, Pate SY, et al. Antibody deficiency secondary to chronic lymphocyte leukemia: should patients be treated with prophylactic replacement immunoglobulin? J Clin Immunol. 2014;34(3):277–82.
Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186–205.
Ilkjær FV, Rasmussen LD, Martin-Iguacel R, Westh L, Katzenstein TL, Hansen A-BE, et al. How to identify common variable immunodeficiency patients earlier: general practice patterns. J Clin Immunol. 2019;39(7):641–52.
Slade CA, Bosco JJ, Binh Giang T, Kruse E, Stirling RG, Cameron PU, et al. Delayed diagnosis and complications of predominantly antibody deficiencies in a cohort of Australian adults. Front Immunol. 2018;9:694.
Bazregari S, Azizi G, Tavakol M, Asgardoon MH, Kiaee F, Tavakolinia N, et al. Evaluation of infectious and non-infectious complications in patients with primary immunodeficiency. Cent Eur J Immunol. 2017;42(4):336–41.
Shehata N, Palda V, Bowen T, Haddad E, Issekutz TB, Mazer B, et al. The use of immunoglobulin therapy for patients with primary immune deficiency: an evidence-based practice guideline. Transfus Med Rev. 2010;24:S28-50.
Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, et al. Update on the use of immunoglobulin in human disease: a review of evidence. J Allergy Clin Immunol. 2017;139(3, Supplement):S1-46.
Elsink K, van Montfrans JM, van Gijn ME, Blom M, van Hagen PM, Kuijpers TW, et al. Cost and impact of early diagnosis in primary immunodeficiency disease: a literature review. Clin Immunol. 2020;213:108359.
Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34–48.
Gathmann B, Goldacker S, Klima M, et al. The German national registry for primary immunodeficiencies (PID). Clin Exp Immunol. 2013;173:372–80.
Edgar JD, Buckland M, Guzman D, et al. The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years’ activity. Clin Exp Immunol. 2014;175:68–78.
Blore J, Haeney MR. Primary antibody deficiency and diagnostic delay. BMJ. 1989;298:516–7.
Ameratunga R, Ahn Y, Jordan A, Lehnert K, Brothers S, Woon S-T. Keeping it in family: the case for considering late-onset combined immunodeficiency a subset of common variable immunodeficiency disorders. Expert Rev Clin Immunol. 2018;14(7):549–56.
Jolles S, Smith DB, Vihn DC, Mallick R, Espinoza G, DeKoven M, Divino V. Risk factors for severe infections in secondary immunodeficiency: a retrospective US administrative claims study in patients with haematological malignancies. Leuk Lymphoma. 2021;63(1):64–73.
Pickett D, Modell V, Leighton I, Modell F. Impact of a physician education and patient awareness campaign on the diagnosis and management of primary immunodeficiencies. Immunol Res. 2008;40:93–4.
Arkwright PD, Gennery AR. Ten warning signs of primary immunodeficiency: a new paradigm is needed for the 21st century. Ann N Y Acad Sci. 2011;1238:7–14.
Kwan A, Abraham RS, Currier R, et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA. 2014;312:729–38.
Holding S, Jolles S. Current screening approaches for antibody deficiency. Curr Opin Allergy Clin Immunol. 2015;15(6):547–55.
de Vries E. Patient-centered screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update. Clin Exp Immunol. 2012;167:108–19.
Jolles S, Borrell R, Zouwail S, Heaps A, Sharp H, Moody M, et al. Calculated globulin (CG) as a screening test for antibody deficiency. Clin Exp Immunol. 2014;177(3):671–8.
Arnold DF, Wiggins J, Cunningham-Rundles C, et al. Granulomatous disease: distinguishing primary antibody disease from sarcoidosis. Clin Immunol. 2008;128:18–22.
Pecoraro A, Jolles S, Crescenzi L, Varricchi G, Marone G, Savoia M, et al. Validation of calculated globulin (CG) as a screening test for antibody deficiency in an Italian university hospital. Curr Pharm Biotechnol. 2018;19(9):728–33.
Hool T, Lim EM, John M, D’Orsogna L, McLean-Tooke A. Calculated globulin as a screening tool for hypogammaglobulinaemia or paraproteins in hospitalized patients. Ann of Clin Biochem. 2021;58(3):236–43.
Holding S, Khan S, Sewell WAC, Jolles S, Dore PC. Using calculated globulin fraction to reduce diagnostic delay in primary and secondary hypogammaglobulinaemias: results of a demonstration project. Ann Clin Biochem. 2015;52(Pt 3):319–26.
Lee AYS, Cassar PM, Johnston AM, Adelstein S. Clinical use and interpretation of serum protein electrophoresis and adjunt assays. Br J H Med (Lond). 2017;78(2):C18-20.
Vavricka SR, Burri E, Beglinger C, Degen L, Manz M. Serum protein electrophoresis: an underused but very useful test. Digestion. 2009;79(4):203–10.
Inmetro - Acreditação de Laboratórios de Análises Clínicas [Internet]. [accessed on December 03, 2022].Available from: http://inmetro.gov.br/Credenciamento/acre_lab_ac.asp
SBPC/ML | Programas da Qualidade (Categoria) PALC [Internet]. [accessed on December 03, 2022]. Available from : http://www.sbpc.org.br/programa-da-qualidade/palc/
Cole TJ. Applied logistic regression. D. W. Hosmer and S. Lemeshow, Wiley, New York, 1989. Statistics in Medicine1991;10(7):1162–3
Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3(1):32–5.
Fluss R, Faraggi D, Reiser B. Estimation of the Youden Index and its associated cutoff point. Biom J. 2005;47(4):458–72.
Jolles S, Chapel H, Litzman J. When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency: a practical approach. Clin Exp Immunol. 2017;188:333–41.
Friman V, Winqvist O, Blimark C, Langerbeins P, Chapel H, Dhalla F. Secondary immunodeficiency in lymphoproliferative malignancies. Hematol Oncol. 2016;34:121–32.
Byrd JC, O’Brien S, James DF. Ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:1278–9.
Casulo C, Maragulia J, Zelenetz AD. Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections. Clin Lymphoma Myeloma Leuk. 2013;13:106–11.
Pac M, Casanova JL, Reisli I, Marodi L. Advances in primary immunodeficiency in Central-Eastern Europe. Front Immunol. 2021;12:667727.
Franco-Jarava C, Colobran R, Mestre-Torres J, Vargas V, Pujol-Borrell R, Hernández-González M. Clinical laboratory standard capillary protein electrophoresis alerted of a low C3 state and lead to the identification of a Factor I deficiency due to a novel homozygous mutation. Immunol Lett. 2016;174:19–22. https://doi.org/10.1016/j.imlet.2016.04.011.
de Piza CFST, Aranda CS, Solé D, Jolles S. Condino-Neto A 2021 Serum protein electrophoresis may be used as a screening tool for antibody deficiency in children and adolescents. Front Immunol. 2021;12:3332.
Gonzalez-Quintela A, Alende R, Gude F, Campos J, Rey J, Meijide LM, et al. Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities. Clin Exp Immunol. 2008;151(1):42–50.
J.M.G. Wilson, G. Jungner. Principles and practice of screening for disease. Public Health Papers, WHO Public Health Papers. 34th ed . 1968.
Dobrow MJ, Hagens V, Chafe R, Sullivan T, Rabeneck L. Consolidated principles for screening based on a systematic review and consensus process. CMAJ. 2018;190(14):E422–9.
Acknowledgements
We thank Dr. Mariangela Correa, Conscient Scientific Consulting, for help with manuscript writing.
Funding
This work received research grants from the Jeffrey Modell Foundation, CSL Behring and Takeda Pharma Ltda as Investigator-initiated research grant (IISR-2020–103,243).
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Study conception and design were executed by CFSTP, SJ, and ACN. Data collection was implemented by CFSTP, CSA, and DS. All authors performed data analysis, manuscript review, and final manuscript approval.
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The University of São Paulo and Federal University of São Paulo Ethics Committees approved the protocol (approval numbers 3.340.392 and 3.499.511, respectively) according to the Brazilian Ministry of Health and the Declaration of Helsinki rules and regulations.
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CFSTP, CSA, DS, and ACN declare no conflict of interests. SJ has received consulting fees, speaker fees, and research grants from CSL Behring, Takeda, and Octapharma. He is a member of the UCB Pharma Data Safety and Management Board.
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de Toledo Piza, C.F.S., Aranda, C.S., Solé, D. et al. Screening for Antibody Deficiencies in Adults by Serum Electrophoresis and Calculated Globin. J Clin Immunol 43, 1873–1880 (2023). https://doi.org/10.1007/s10875-023-01536-1
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DOI: https://doi.org/10.1007/s10875-023-01536-1