Using calculated globulin fraction to reduce diagnostic delay in primary and secondary hypogammaglobulinaemias: results of a demonstration project

Ann Clin Biochem. 2015 May;52(Pt 3):319-26. doi: 10.1177/0004563214545791. Epub 2014 Jul 14.


Background: Median diagnostic delay of five to six years seen in primary hypogammaglobulinaemia results in morbidity including bronchiectasis. Patients typically have multiple health care encounters and blood tests before the diagnosis is considered. We report outcomes from using the difference between total protein and albumin (globulin fraction) to reduce diagnostic delay in unsuspected hypogammaglobulinaemia.

Methods: A prospective >5 year programme in the setting of a National Health Services Hospital Blood Sciences pathology service processing serum samples from primary and secondary care. Patients with globulin fraction below the first percentile were reviewed in the context of supplied clinical details. Immunoglobulin measurements were performed in selected patients.

Results: Of 2,910,850 globulin fractions 27,304 (0.9%) were below the 1st percentile globulin fraction (<18 g/L). After exclusions, 933 (3% of these) had immunoglobulins measured. Of these, 292 had IgG < 5 g/L, 186 < 4 g/L and 80 < 3 g/L, giving respective positive predictive values of 31%, 20% and 8.6%. Positive predictive value for common variable immunodeficiency was 1.3%. We identified 12 new cases of common variable immunodeficiency, 10 new haematological disorders and 20 hypogammaglobulinaemias secondary to medication. Locally derived cut-offs are required as small differences between analysers have a significant effect on screen-positive rates.

Conclusions: Use of a 1st percentile globulin fraction improved early detection of hypogammaglobulinaemia. This is a useful adjunct to alert clinicians to unsuspected hypogammaglobulinaemia but should not replace immunoglobulin measurement. Patients with globulin fraction below the first percentile should be reviewed for possible hypogammaglobulinaemia.

Keywords: Sensitivity and specificity; common variable immunodeficiency; diagnostic delay; globulins; hypogammaglobulinaemia; lymphoproliferative disease; primary immunodeficiency; screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Agammaglobulinemia / blood*
  • Agammaglobulinemia / diagnosis*
  • Globulins / analysis*
  • Humans
  • Immunoglobulin G / blood*
  • Prospective Studies
  • Retrospective Studies
  • Time Factors


  • Globulins
  • Immunoglobulin G