Catherine R. Weiler

Prevention of Mast Cell Activation Disorder-Associated Clinical Sequelae of Excessive Prostaglandin D2 Production

Background: Patients with systemic mastocytosis have increased numbers of mast cells in the bone marrow and other organs, such as the liver, spleen, gastrointestinal tract and skin. Symptoms result from the local and remote effects of mediator release from mast cells and from the local effects of increased mast cell numbers in various organs. Patients with mast cell activation experience many of the same clinical symptoms as do patients with systemic mastocytosis from chronic or spontaneous release of mast cell mediators. We report 4 patients with mast cell activation symptoms from selective release of prostaglandin (PG) D2, but not histamine, and their improvement with aspirin therapy. Methods: Bone marrow biopsy specimens obtained from 4 patients with symptoms suggestive of mastocytosis were examined by tryptase immunostaining. Baseline levels of serum tryptase and urinary 11β-PGF2α and N-methylhistamine were obtained. In 2 of the 4 patients, urinary 11β-PGF2α and N-methylhistamine samples were also measured during acute symptoms. Results: Baseline increase in urinary excretion of the PGD2 metabolite 11β-PGF2α was found in 2 patients. In the remaining 2 patients, baseline levels of urinary 11β-PGF2α and N-methylhistamine were normal, but during acute symptoms, the excretion of 11β-PGF2α increased markedly. Treatment with aspirin resulted in normalization of 11β-PGF2α excretion in the 2 patients with elevated baseline levels and in prevention of symptoms in all 4 patients. Conclusions: These results suggest that mast cell activation may be manifested by a selective excessive release of PGD2. These patients respond to administration of aspirin but not to antihistamines.

Clinical and laboratory characteristics of 75 patients with specific polysaccharide antibody deficiency syndrome

BACKGROUND There are limited studies of large cohorts of patients with specific polysaccharide antibody deficiency (SPAD) syndrome. OBJECTIVE To study the clinical and laboratory characteristics of patients with specific polysaccharide antibody deficiency syndrome. METHODS We retrospectively studied 75 patients with total IgG levels of at least 500 mg/dL and fewer than 9 of 12 responses to vaccination with pneumococcal vaccine polyvalent. Exclusion criteria included an IgG level less than 500 mg/dL, established immunodeficiency syndrome, and secondary immunodeficiency. RESULTS The most common clinical presentation was frequent infections (n = 69; 92%), including sinusitis (n = 53; 77%), pneumonia (n = 29; 42%), ear infections (n = 18; 26%), and bronchitis (n = 19; 28%). Other presentations were systemic infections (n = 5; 7%), autoimmune or rheumatic diseases (n = 6; 8%), and chronic diarrhea (n = 4; 5%). The median IgG2 level of patients with no response to pneumococcal vaccine polyvalent tended to be lower than that of patients with at least 1 response (150 vs 193 mg/dL, respectively; P = .06). There was no association between total IgG level (categorized as 500-600 or > or = 600 mg/dL) and frequency of infection (P = .43). Patients with fewer responses to pneumococcal vaccine polyvalent and a higher frequency of infections were more likely to receive intravenous immunoglobulin (IVIG) therapy (P = .01 and .003, respectively). Treatment with IVIG significantly reduced the number of infections (P < .001). CONCLUSION Patients with no response to pneumococcal vaccine polyvalent tended to have lower IgG2 levels; those with fewer responses were more likely to receive IVIG therapy.

Eosinophil viability during immunoglobulin-induced degranulation.

Eosinophil adhesion and degranulation appear to be associated with cell death. Eosinophils bound avidly and degranulated with secretory immunoglobulin A (slgA)‐ and IgG‐coupled Sepharose 4B beads but bound poorly and did not degranulate with ovalbumin beads. Through the use of dye staining, we found that about 50% of the bound eosinophils were dead by 4 h, regardless of the protein coating. Colchicine and reduced calcium concentration inhibited binding to beads and eosinophil degranulation in a concentration‐dependent manner but did not decrease the percentages of dead bound eosinophils. Electron microscopy showed that eosinophils bound to and spread over bead surfaces. Typical granule exocytosis with release of membrane‐free granules occurred in about 20% of bound eosinophils. Eosinophil degeneration and lysis with release of membrane‐coated granules occurred in about 50% of bound eosinophils; often only membrane‐bound granules were present. Therefore, bound eosinophils degranulate both by classical exocytosis and by release after cytolytic degeneration. By increasing the numbers of bound cells, both IgG and sIgA increase the numbers of dying cells, J. Leukoc. Biol. 60: 493–501; 1996.

Genetic Test Indications and Interpretations in Patients With Hereditary Angioedema

Patients with hereditary angioedema (HAE) present with recurrent, circumscribed, and self-limiting episodes of tissue or mucous membrane swelling caused by C1-inhibitor (CI-INH) deficiency. The estimated frequency of HAE is 1:50,000 persons. Distinguishing HAE from acquired angioedema (AAE) facilitates therapeutic interventions and family planning or testing. Patients with HAE benefit from treatment with attenuated androgen, antifibrinolytic agents, and C1-INH concentrate replacement during acute attacks. HAE is currently recognized as a genetic disorder with autosomal dominant transmission. Other forms of inherited angioedema that are not associated with genetic mutations have also been identified. Readily available tests are complement studies, including C4 and C1-esterase inhibitor, both antigenic and functional C1-INH. These are the most commonly used tests in the diagnosis of HAE. Analysis of C1q can help differentiate between HAE and AAE caused by C1-INH deficiency. Genetic tests would be particularly helpful in patients with no family history of angioedema, which occurs in about half of affected patients, and in patients whose C1q level is borderline and does not differentiate between HAE and AAE. Measuring autoantibodies against C1-INH also would be helpful, but the test is available in research laboratories only. Simple complement determinations are appropriate for screening and diagnosis of the disorder.

Immunoglobulin therapy: history, indications, and routes of administration

The primary use of serum was as an “antitoxin” for specific infectious diseases (by passive transfer of immunity). Early “antitoxin” preparations were obtained from horses and other animals. Human serum was used in early 1900 for protection against some viruses. 2 Cohn et al. 3 were the first to devise a method for plasma fractionation, which enriched for immunoglobulin (IG). Their technique was later modified by their colleagues for higher IG yield. 4–6

Common Variable Immunodeficiency: Test Indications and Interpretations

Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder that can present with multiple phenotypes, all of which are characterized by hypogammaglobulinemia, in a person at any age. A specific genetic defect that accounts for all CVID phenotypes has not been identified, and it is likely that several distinct genetic disorders with similar clinical presentations are responsible for the observed variation. In this review, we summarize the known genetic mutations that give rise to hypogammaglobulinemia and how these gene products affect normal or abnormal B-cell development and function, with particular emphasis on CVID. Additionally, we describe specific phenotypic and genetic laboratory tests that can be used to diagnose CVID and provide guidelines for test interpretation and subsequent therapeutic intervention.

Hypersensitivity to progesterone-in-oil after in vitro fertilization and embryo transfer

OBJECTIVE To report the occurrence and management of pulmonary compromise, marked leukocytosis, and eosinophilia in a patient receiving P-in-oil after IVF and embryo transfer. DESIGN Case report.A tertiary referral reproductive medicine unit. PATIENT(S) A 29-year-old patient receiving P-in-oil supplementation after IVF embryo transfer. INTERVENTION(S) Extensive diagnostic testing and surveillance for hypersensitivity to P in sesame oil; development of an alternative oil-based P-in-oil suspension. MAIN OUTCOME MEASURE(S) Tolerance of alternative P vehicle; clinical pregnancy. RESULT(S) The patient tolerated an alternative P oil vehicle and successfully achieved a clinical pregnancy after frozen embryo transfer. CONCLUSION(S) Although rare, hypersensitivity reactions may occur in patients receiving P-in-oil supplementation after IVF embryo transfer. Testing for tolerance and subsequent use of alternative P vehicles may be an effective strategy in managing patients with sensitivity to P-in-oil.

Increased Numbers of Eosinophils, Rather Than Only Etiology, Predict Histologic Changes in Patients With Esophageal Eosinophilia

BACKGROUND & AIMS It can be a challenge to differentiate individuals with eosinophilic esophagitis (EoE) from those with gastroesophageal reflux disease (GERD). We investigated differences in histologic and eosinophil patterns and numbers of mast cells between patients with these disorders. METHODS We performed histologic analyses and immunohistochemical assays for eosinophil-derived neurotoxin (EDN), major basic protein (MBP), and tryptase, using biopsy samples from 10 patients with GERD (positive results from a pH study and response to proton pump inhibitors), Barretts esophagus, or EoE (negative results from a pH study and positive response to budesonide). Patients were matched for degree of eosinophilia. RESULTS Samples from patients with EoE, GERD, or Barretts esophagus had similar increases in concentrations of eosinophils. Patients with GERD or EoE did not differ in amount of basal zone hyperplasia, microabscesses, spongiosis, eosinophil distribution, maximum eosinophils/high-power field (HPF), or composite histologic scores. Samples from all 3 groups had high levels of EDN and MBP; the levels of eosinophil products were correlated (ρ = 0.93). Extracellular staining for EDN was greater than intracellular staining (2.67 of 3 vs 1.86 of 3); levels tended to be greater in samples from patients with EoE than GERD (P = .05) or Barretts esophagus (P = .06). Detection of EDN correlated with peak numbers of eosinophils/HPF (ρ = 0.6 for intracellular and extracellular staining). Peak numbers of tryptase-positive mast cells/HPF were significantly greater in samples from patients with EoE than GERD or Barretts esophagus (P = .01 and .005, respectively). The Spearman correlation between eosinophil and mast cell density was a ρ value of 0.2. CONCLUSIONS Biopsy samples from patients with GERD and EoE, matched for esophageal eosinophilia, have similar changes in histology and levels of EDN and MBP, whereas mast cells from patients with EoE have higher levels of these products. The presence of esophageal eosinophils, rather than etiology, could be the most important determinant of epithelial response.

Eosinophilic Esophagitis: Is It All Allergies?

Eosinophilic esophagitis (EE) is an increasingly recognized disorder in the adult population, most often manifested by symptoms of dysphagia and food impaction. Mechanisms involving eotaxin-3, interleukin 5, and signal transducer and activator of transcription 6 have been studied and may represent future therapeutic targets. Patients commonly have a personal and family history of atopy, and both food allergies and aeroallergens have also been investigated as triggers of EE. Traditional allergy-testing methods, including skin prick testing and specific IgE testing, have been used to identify food and environmental allergies. However, new studies suggest that patch testing could add to diagnostic accuracy in EE because the disorder might not be a classic type I allergic response. Although studies of treatment of adults with EE have thus far focused on swallowed fluticasone proprionate, many trials in children have assessed the efficacy of food elimination and elemental diets. These diets, which have been extremely successful in reducing symptoms, have also been shown to induce histological improvement and remission. No similar studies have been conducted in adults; the tolerability of such an intervention may prove more difficult in this population. This article reviews the underlying pathophysiology of EE and describes evolving options for more accurately identifying food and environmental allergies. We also discuss the pediatric trials using food elimination and avoidance diets and suggest that this type of intervention may be an important area of future research in the adult population.

Mast Cell Activation Syndrome: Improved Identification by Combined Determinations of Serum Tryptase and 24-Hour Urine 11β-Prostaglandin2α

BACKGROUND Mast cell activation syndrome (MCAS) describes patients with episodes of mast cell mediator release, with negative bone marrow biopsy results, and the failure to meet the criteria for systemic mastocytosis. OBJECTIVE Identify elevation of mast cell mediators of patients with MCAS. METHODS We performed a retrospective study of 25 patients with MCAS who were evaluated at Mayo Clinic from 2006 to 2012. Patients were reviewed for MCAS symptoms and mast cell mediators, including serum tryptase and 24-hour urine N-methyl histamine (N-MH) and 11β-prostaglandin-F₂α (11β-PGF₂α). The study was approved by the institutional review board. RESULTS Urinary 11β-PGF₂α was the most frequently elevated product in MCAS of our 25-patient cohort. Flushing and pruritus had the greatest correlation with elevation of 24-hour urine 11β-PGF₂α value at baseline. The serum tryptase level was elevated in 10 patients, whereas the N-MH level was elevated with 2 patients. Eight of 9 patients with MCAS and with elevated 24-hour urine 11β-PGF₂α who underwent aspirin therapy and follow-up urinary studies had normalization of this mediator (1 patient did not have a follow-up urine study). Six of these 9 patients with MCAS who underwent aspirin therapy had symptomatic improvement. CONCLUSION We recommend measurement of 24-hour urine 11β-PGF₂α and serum tryptase levels of patients with symptoms suggestive of MCAS. Measurement of 24-hour urine 11β-PGF₂α and serum tryptase levels can help avoid misdiagnosis and overinterpretation of MCAS symptoms in clinical practice. Given that an elevation of 24-hour urine N-MH level was found only in 2 patients, measurement of this mediator may be less helpful in diagnosing MCAS. We recommend aspirin therapy for patients with MCAS and with elevated 24-hour urine 11β-PGF₂α levels.