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.

Outcomes of eosinophilic esophagitis in patients managed in a multidisciplinary clinic.

Background: Eosinophilic esophagitis is a complex disease with an increasing prevalence. Multidisciplinary teams are often needed to manage this difficult-to-treat condition. Objective: To observe the clinical and histologic outcomes of patients with eosinophilic esophagitis after management in a multidisciplinary clinic. Methods: An observational, retrospective chart review was conducted to include all patients referred to the Walter Reed National Military Medical Center multidisciplinary eosinophilic esophagitis clinic between August 2012 and February 2021. Only patients who had at least one esophagogastroduodenoscopy before referral, one or more visits and endoscopy after multidisciplinary management, and documented clinical symptoms were included. Statistical analysis was performed by using McNemar and Wilcoxon tests. Results: A total of 103 patients were included in the study, with a mean age at diagnosis of 17.9 years. Management in the multidisciplinary clinic was associated with a reduction in solid-food dysphagia by 70.9%, poor growth by 70.8%, and emesis or regurgitation by 87.5%. We observed that 48.5% and 62.1% had histologic remission (<15 eosinophils/hpf) on the initial and any post-multidisciplinary endoscopy, respectively. Only seven patients (5.8%) with two or more visits and endoscopies did not achieve histologic remission. More than two-thirds of the patients (68.9%) required combination therapy to achieve remission. Conclusion: Although an observational study, these findings may suggest that the management of patients with eosinophilic esophagitis in a multidisciplinary clinic may improve the likelihood of clinical and histologic remission. Targeted management with a multidisciplinary approach may reduce overall morbidity and slow disease progression; however, more research is needed.

Stinging Ant Anaphylaxis: Advances in Diagnosis and Treatment.

Stinging ants represent a wide range of over 200 different species across the world, of which Solenopsis, Myrmecia, Pogonomyrmex, and Brachyponera genera account for a substantial economic and healthcare burden. S. invicta (red imported fire ant [IFA]) and M. pilosula (jack jumper ant [JJA]) are 2 species of high clinical importance, known to cause anaphylaxis in humans, with numerous reported fatalities. Diagnostic testing should be performed in patients with a history of a systemic reaction with skin testing and/or in vitro specific immunoglobulin E (IgE) testing. In vitro testing is commercially available for IFA through whole-body extract specific IgE and JJA venom-specific IgE, but not widely available for other stinging ant species. Commercial venom component testing for IFA and JJA is currently not available. Patients with a clinical history and positive specific IgE testing should undergo treatment with specific immunotherapy, which is currently available for IFA and JJA. Buildup may be performed using conventional, semi-rush, rush, or ultra-rush schedules with similar risk profiles for IFA. Optimal duration for whole=body extract immunotherapy for IFA and specific JJA venom immunotherapy is not well studied, but generally recommended for at least 3 to 5 years. Sting challenges are used in research settings, primarily to assess treatment efficacy of immunotherapy.

Multisystem Inflammatory Syndrome in Children (MIS-C), a Post-viral Myocarditis and Systemic Vasculitis-A Critical Review of Its Pathogenesis and Treatment.

MIS-C is a newly defined post-viral myocarditis and inflammatory vasculopathy of children following COVID-19 infection. This review summarizes the literature on diagnosis, parameters of disease severity, and current treatment regimens. The clinical perspective was analyzed in light of potential immunopathogenesis and compared to other post-infectious and inflammatory illnesses of children affecting the heart. In this paradigm, the evidence supports the importance of endothelial injury and activation of the IL-1 pathway as a common determinant among MIS-C, Kawasaki disease, and Acute Rheumatic fever.