Abstract
Objectives
The value of the serum protein gap (PG, difference between total protein and albumin) in the detection of hyper- or hypogammaglobulinemia is not well established. We assessed the performance of PG for the detection of hyper- or hypogammaglobulinemia in a large sample of patients.
Methods
We reviewed all paired measurements of serum total protein, albumin, quantitative immunoglobulins, and serum protein electrophoresis tested between March 2014 and June 2017 at the Eastern Ontario Regional Laboratory Association. Sensitivity, specificity, positive predictive value, negative predictive value and likelihood ratios of PG at thresholds between 18 and 44 g/L for the detection of hyper- and hypogammaglobulinemia were assessed.
Results
There were 19,575 and 5,426 simultaneous paired data points to assess hyper- and hypogammaglobulinemia identified by serum protein electrophoresis (SPE) and nephelometry, respectively. The mean PG was 36.3 g/L (SD 8.6). The prevalence of hypergammaglobulinemia (>16 g/L by SPE) and hypogammaglobulinemia (IgG <7 g/L) was 21.9 and 5.5%, respectively. High PG (≥38 g/L) had sensitivity and specificity of 76.2 and 71.5% respectively for hypergammaglobulinemia. PG ≥38 g/L had a negative predictive value (NPV) of 93.1% for monoclonal, and 96.9% for polyclonal gammopathy. A PG threshold of ≤18 g/L had of sensitivity of 0.4%, specificity of 100%, PPV of 100% and NPV of 80.1% to detect hypogammaglobulinemia (IgG <7 g/L).
Conclusions
High and low PG values were not sensitive in detecting hyper- or hypogammaglobulinemia, although negative predictive values were high for both. Performance of PG should be further evaluated prospectively in specific populations at risk of for abnormal IgG levels.
-
Research funding: None declared.
-
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
-
Competing interests: Authors state no conflict of interest.
-
Informed consent: Informed consent was obtained from all individuals included in this study.
-
Ethical approval: The study was approved by the Ottawa Hospital Research Institute Research Ethics Board (under the protocol number 20170437-01H).
References
1. 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;177:671–8. https://doi.org/10.1111/cei.12369.Search in Google Scholar
2. Stohl, W, Kenol, B, Kelly, AJ, Correa, AA, Panush, RS. Elevated serum globulin gap as a highly reliable marker of elevated erythrocyte sedimentation rate in patients with systemic rheumatic diseases. Semin Arthritis Rheum 2019;49:485–92. https://doi.org/10.1016/j.semarthrit.2019.05.001.Search in Google Scholar
3. Doweiko, JP, Nompleggi, DJ. Reviews: role of albumin in human physiology and pathophysiology. J Parenter Enteral Nutr 1991;15:207–11. https://doi.org/10.1177/0148607191015002207.Search in Google Scholar
4. Vavricka, SR, Burri, E, Beglinger, C, Degen, L, Manz, M. Serum protein electrophoresis: an underused but very useful test. Digestion 2009;79:203–10. https://doi.org/10.1159/000212077.Search in Google Scholar
5. Dupuis, MM, Paul, B, Loitsch, G, Mathews, P, Feinberg, D, Barak, I, et al.. Gamma gap: a point-of-care test that correlates with disease burden and treatment response in multiple myeloma. JCO Oncol Pract 2020;16:e751–7. https://doi.org/10.1200/JOP.19.00517.Search in Google Scholar
6. Thakkinstian, A, Tran, H, Reeves, G, Murch, S, Attia, J. A clinical decision rule to aid ordering of serum and urine protein electrophoresis for case-finding of paraproteins in hospitalized inpatients. J Gen Intern Med 2008;23:1688–92. https://doi.org/10.1007/s11606-008-0712-z.Search in Google Scholar
7. 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;52:319–26. https://doi.org/10.1177/0004563214545791.Search in Google Scholar
8. 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 [Internet]. Curr Pharmaceut Biotechnol 2018;19:728–33. Available from: https://www.eurekaselect.com/164507/article [Cited 19 Jul 2020].10.2174/1389201019666180808163311Search in Google Scholar
9. Phelps, MA, Levitt, MA. Pretest probability estimates: a pitfall to the clinical utility of evidence‐based medicine? Acad Emerg Med 2004;11:692–4. https://doi.org/10.1197/j.aem.2003.08.022.Search in Google Scholar
10. IBM Corp. IBM SPSS statistics for Windows, version 24.0. Armonk, NY: IBM Corp.; 2016.Search in Google Scholar
11. Rajkumar, SV, Dimopoulos, MA, Palumbo, A, Blade, J, Merlini, G, Mateos, MV, et al.. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538–48. https://doi.org/10.1016/s1470-2045(14)70442-5.Search in Google Scholar
12. Dispenzieri, A, Gertz, MA, Therneau, TM, Kyle, RA. Retrospective cohort study of 148 patients with polyclonal gammopathy. Mayo Clin Proc 2001;76:476–87. https://doi.org/10.4065/76.5.476.Search in Google Scholar PubMed
13. Yang, M, Xie, L, Liu, X, Hao, Q, Jiang, J, Dong, B. The gamma gap predicts 4-year all-cause mortality among nonagenarians and centenarians. Sci Rep 2018;8:1046. https://doi.org/10.1038/s41598-018-19534-4.Search in Google Scholar PubMed PubMed Central
14. Tannou, T, Koeberle, S, Manckoundia, P, Aubry, R. Multifactorial immunodeficiency in frail elderly patients: contributing factors and management. Médecine Mal Infect 2019;49:167–72. https://doi.org/10.1016/j.medmal.2019.01.012.Search in Google Scholar PubMed
15. Cowan, J, Do, TL, Desjardins, S, Ramotar, K, Corrales-Medina, V, Cameron, DW. Prevalence of hypogammaglobulinemia in adult invasive pneumococcal disease. Clin Infect Dis 2018;66:564–9. https://doi.org/10.1093/cid/cix836.Search in Google Scholar PubMed
16. Wadhera, RK, Rajkumar, SV. Prevalence of monoclonal gammopathy of undetermined significance: a systematic review. Mayo Clin Proc 2010;85:933–42. https://doi.org/10.4065/mcp.2010.0337.Search in Google Scholar PubMed PubMed Central
Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2020-1286).
© 2020 Walter de Gruyter GmbH, Berlin/Boston
