Standardized indolent systemic mastocytosis evaluations across a health care system: implications for screening accuracy.

ABSTRACT: Timely diagnosis of systemic mastocytosis (SM) remains challenging because of care heterogeneity. We implemented a standardized approach for SM screening and diagnosis using a novel health care system-wide international screening registry. A retrospective analysis assessed rates of SM, cutaneous mastocytosis (CM), and molecular diagnoses before and 2 years after care standardization. The accuracy of individual and combined SM screening tests, basal serum tryptase (BST) ≥11.5 and ≥20.0 ng/mL, REMA ≥2, monomorphic maculopapular CM (MPCM), and elevated BST based upon tryptase genotype, was analyzed. Tryptase genotyping and high-sensitivity KIT p.D816V testing increased substantially 2 years after care standardization. SM diagnoses doubled from 47 to 94, and KIT p.D816V molecular diagnoses increased from 24 to 79. Mean BST and KIT p.D816V variant allele frequency values were significantly lower in patients diagnosed after standardization. Hereditary-alpha tryptasemia prevalence was increased in SM before care standardization (4/30 [13.3%]) but reflected the general population prevalence 2 years later at (5/76 [6.6%]). Elevated BST based upon genotype and BST ≥11.5 ng/mL had the highest sensitivities at 84.2% and 88.3%, respectively. The presence of monomorphic MPCM, elevated BST based upon tryptase genotype, and the combination of REMA ≥2 with elevated BST based upon tryptase genotype had specificities >90%. BST >20.0 ng/mL had low sensitivity and specificity and was not required to establish any indolent SM (ISM) diagnosis. Care standardization increased SM diagnosis rates, particularly in patients with low BSTs. Stratifying BST based upon genotype had the best overall sensitivity and specificity of any ISM screening test and improved the REMA score specificity.

Immunodeficiency: Complement disorders.

The complement system is an important component of innate and adaptive immunity that consists of three activation pathways. The classic complement pathway plays a role in humoral immunity, whereas the alternative and lectin pathways augment the innate response. Impairment, deficiency, or overactivation of any of the known 50 complement proteins may lead to increased susceptibility to infection with encapsulated organisms, autoimmunity, hereditary angioedema, or thrombosis, depending on the affected protein. Classic pathway defects result from deficiencies of complement proteins C1q, C1r, C1s, C2, and C4, and typically manifest with features of systemic lupus erythematosus and infections with encapsulated organisms. Alternative pathway defects due to deficiencies of factor B, factor D, and properdin may present with increased susceptibility to Neisseria infections. Lectin pathway defects, including Mannose-binding protein-associated serine protease 2 (MASP2) and ficolin 3, may be asymptomatic or lead to pyogenic infections and autoimmunity. Complement protein C3 is common to all pathways, deficiency of which predisposes patients to severe frequent infections and glomerulonephritis. Deficiencies in factor H and factor I, which regulate the alternative pathway, may lead to hemolytic uremic syndrome. Disseminated Neisseria infections result from terminal pathway defects (i.e., C5, C6, C7, C8, and C9). Diagnosis of complement deficiencies involves screening with functional assays (i.e., total complement activity [CH50], alternative complement pathway activity [AH50], enzyme-linked immunosorbent assay [ELISA]) followed by measurement of individual complement factors by immunoassay. Management of complement deficiencies requires a comprehensive and individualized approach with special attention to vaccination against encapsulated bacteria, consideration of prophylactic antibiotics, treatment of comorbid autoimmunity, and close surveillance.