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

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.

Use of serum free light chain analysis and urine protein electrophoresis for detection of monoclonal gammopathies.

BACKGROUND: Serum free light chain (FLC) analysis is used in the prognostic assessment and monitoring of patients with monoclonal gammopathies (MG). Its use in detection of MG is less widespread despite good sensitivity for diseases poorly detected by serum protein electrophoresis (SPE), e.g., FLC disease and AL amyloidosis. FLC analysis may facilitate earlier diagnosis in these diseases. However, if replacing urine protein electrophoresis (UPE) in an initial screening algorithm, this must be balanced against any loss of detection of Bence Jones proteinuria (BJP). METHODS: We assessed the effect of replacing UPE with FLC. Sensitivity of FLC for BJP was assessed in 126 clinical cases where UPE and FLC analyses were performed. Impact on disease detection was assessed from 753 patient sera tested by SPE and FLC and 128 patients matched associated urine samples. RESULTS: Sensitivity of FLC for BJP was 98%. Use of FLC in routine testing increased the number of MG detected by 7%. CONCLUSIONS: Using FLC alongside or in place of UPE can give clinical benefit through earlier diagnosis and hence treatment earlier in the patients' disease.

Secondary systemic lupus erythematosus: an analysis of 4 cases of uncontrolled hereditary angioedema.

The association of systemic lupus erythematosus and hereditary angioedema (HAE) has formed the basis of numerous case reports and is hypothesised to result from consumption of complement C4 with consequent impaired clearance of apoptotic cells. We describe the development of frank lupus or lupus-like syndrome in four HAE patients with uncontrolled angioedema and low levels of serum C4. Measures that limit hypocomplementaemia in HAE may reduce the incidence of secondary SLE.