Calculated Globulin: Early Detection of Immunodeficiency

Serum calculated globulin (cGlob) (total protein – albumin) reflects immunoglobulins. We sought to validate cGlob as an aid to diagnosis of CVID using a large sample of patients with connected diagnostic testing from a national reference laboratory. Simultaneous total protein and albumin tests from 2023 determined cGlob. Results for quantitative immunoglobulins, IgG and IgA subclasses, serum protein electrophoresis (SPEP), and immunofixation from one year before or after cGlob were obtained. For repeat testing, the first instance of low cGlob in 2023 was the index date; if no low cGlob was observed in 2023, the patient’s first 2023 cGlob was used as the index. All group results were reported with median and first and third quartiles (Q1 and Q3). A sub-analysis was performed to identify a patient’s time to first diagnosis of CVID using ICD-10 codes on test orders. 28,041,809 patients had both albumin and total protein results in 2023. When observed in combination, 86.9% of patients with cGlob ≥1.8 g/dL had IgG, IgM, and IgA all within normal ranges compared with only 35.4% of patients with low cGlob. Only 0.12% of the full cohort were tested for IgG subclasses (n = 32,529 patients) and 0.01% for IgA subclasses (n = 2,580); only 0.7% (n = 195,768 patients) also had serum protein electrophoresis, and a smaller proportion had immunofixation performed within a year of cGlob (n = 128,923 (0.5%)), where 3.3% (n = 4,308) had a low cGlob. In the longitudinal sub-analysis, only 1.33% of the full cohort (n = 373,870 patients) had all three IgG, IgM, and IgA tested within one year of their index cGlob, 5.84% of which had a low cGlob (n = 21,817). 3,426 patients were identified who had a CVID ICD-10 code on a test order after an instance of a low cGlob. Median number of days between first low cGlob and first CVID ICD-10 was 1,089.0 days [466.0, 1,827.0], a 3-year delay. In conclusion, low cGlob was associated with low immunoglobulins. Only a very small minority of low cGlob patients had further laboratory evaluation within 1 year. Median time to CVID diagnosis following a low cGlob was 3 years. Laboratory investigation of low cGlob could accelerate diagnosis of CVID.