Karen Binkley

Hereditary angioedema with normal C1 inhibitor function: consensus of an international expert panel.

A new form of hereditary angioedema (HAE) with normal C1 inhibitor (C1INH) was first described in 2000. The lack of clear diagnostic criteria, the heterogeneity among affected patients, and the varying names given to this disease have led to substantial confusion among both physicians and patients. This study was designed to bring more clarity to the diagnosis and potential treatment of HAE with normal C1INH. An international symposium of experts was convened to review the field and develop consensus opinions that could help clinicians who evaluate and manage these patients. Criteria were developed for the diagnosis of HAE with normal C1INH in patients with recurrent angioedema in the absence of concurrent urticaria. In addition, potential therapeutic strategies are discussed. The consensus criteria developed during this symposium will allow physicians to better diagnose and treat patients with HAE with normal C1INH.

Idiopathic environmental intolerance. Part 1: A causation analysis applying Bradford Hill's criteria to the toxicogenic theory

Idiopathic environmental intolerance (IEI) is a descriptor for a phenomenon that has many names including environmental illness, multiple chemical sensitivity and chemical intolerance. Toxicogenic and psychogenic theories have been proposed to explain IEI. This paper presents a causality analysis of the toxicogenic theory using Bradford Hill’s nine criteria (strength, consistency, specificity, temporality, biological gradient, biological plausibility, coherence, experimental intervention and analogy) and an additional criteria (reversibility) and reviews critically the scientific literature on the topic. The results of this analysis indicate that the toxicogenic theory fails all of these criteria. There is no convincing evidence to support the fundamental postulate that IEI has a toxic aetiology; the hypothesised biological processes and mechanisms are implausible.

Canadian hereditary angioedema guideline

Hereditary angioedema (HAE) is a disease which is associated with random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased Health Related Quality of Life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada is neither optimal nor uniform across the country. It lags behind other countries where there are more organized models for HAE management, and where additional therapeutic options are licensed and available for use. The objective of this guideline is to provide graded recommendations for the management of patients in Canada with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. It is anticipated that by providing this guideline to caregivers, policy makers, patients and their advocates, that there will be an improved understanding of the current recommendations regarding management of HAE and the factors that need to be considered when choosing therapies and treatment plans for individual patients. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency physicians, gastroenterologists, dentists and otolaryngologists, who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.

Carbon dioxide inhalation challenges in idiopathic environmental intolerance.

BACKGROUND Idiopathic environmental intolerance (IEI) is associated with unexplained physical symptoms, which overlap considerably with those of panic disorder (PD). OBJECTIVE This study tested the hypothesis that patients with symptoms to suggest IEI exhibit features of PD in response to nonnoxious environmental stimuli. METHODS A single-blind, case-control 35% carbon dioxide inhalation challenge was conducted at a university-based occupational health unit with the use of standardized psychologic questionnaires involving 36 patients with IEI and 37 healthy control subjects. The main outcome measures included panic attack symptoms and scores on the Anxiety Sensitivity Index, a measure of panic-related anxiety. RESULTS Patients with IEI scored significantly higher on the Anxiety Sensitivity Index than control subjects did (P <.05). Significantly more patients with IEI (71%) than control subjects (26%) fulfilled panic attack criteria after carbon dioxide (P <.001). Physiologic responses to the challenge were not significantly different between groups. CONCLUSIONS Results suggest that, similar to patients with PD, patients with IEI display high anxiety sensitivity and in response to carbon dioxide inhalation tend to experience heightened anxiety and panic attacks.

Genetic analysis of Factor XII and bradykinin catabolic enzymes in a family with estrogen-dependent inherited angioedema

BACKGROUND Recent studies reported a gain-of-function mutation in the gene encoding coagulation Factor XII (F12) among 5 German and French families with estrogen-associated angioedema who share a common ancestor. The role of this factor, additional pathways that might contribute to increased bradykinin levels, or both remain to be determined in other families with estrogen-dependent or estrogen-associated inherited angioedema. OBJECTIVE The purpose of this study was to determine whether mutations in F12 and polymorphisms in the genes encoding aminopeptidase P (APP) and angiotensin I-converting enzyme (ACE), which have been associated with increased bradykinin levels, contribute to estrogen-dependent inherited angioedema in a large family of Italian origin. METHODS We screened the coding regions of F12 and the gene encoding membrane-bound APP (XPNPEP2), for genetic variants in the 3 affected female subjects. In addition, we genotyped this family for the insertion/deletion polymorphism in the ACE gene, which accounts for variable ACE levels. RESULTS The 3 affected female subjects all have the threonine-to-lysine (Thre328Lys) mutation, which is associated with higher Factor XII activity. In addition, they have at least one A allele of rs3788853 at the XPNPEP2 locus, which is associated with lower APP activity, and at least one I allele in ACE, which is associated with reduced ACE activity. CONCLUSION A missense mutation in F12 is present in the 3 affected female subjects of this family with estrogen-dependent inherited angioedema. In addition, these affected females have polymorphisms associated with lower levels of both APP and ACE, the major enzymes responsible for bradykinin degradation. Thus, our study suggests that multiple genes might contribute to estrogen-dependent or estrogen-associated inherited angioedema and explain some of the observed heterogeneity.

Factor XII mutations, estrogen-dependent inherited angioedema, and related conditions.

The clinical, biochemical and genetic features of the conditions known as estrogen-dependent inherited angioedema, estrogen-associated angioedema, hereditary angioedema with normal C-1 inhibitor, type III angioedema, or factor XII angioedema are reviewed. Discussion emphasizes pathogenesis, diagnosis, and management.

Generalized allergic reactions during anesthesia

Twenty-eight adults with a history of a generalized allergic reaction during anesthesia were investigated. The reactions were systemic in 23 adults, urticaria/angioedema in four, and bronchial obstruction in one adult. The study population and an additional 35 subjects with a history of use of thiopental during anesthesia but without reactions were investigated by methods including thiopental skin test, succinylcholine skin test, and IgE RAST for antibodies to thiopental, succinylcholine, or latex. Among the 28 patients with reactions, 17 had positive thiopental skin tests; 14/28 reactors and 1/35 of the control group had an IgE thiopental RAST value greater than 2 SD above the mean for control sera from ragweed-allergic subjects. The one control subject with a positive thiopental RAST also was the only control subject with a positive thiopental skin test. IgE succinylcholine RAST was negative in all 23 reactor sera tested. The IgE latex RAST was strongly positive in one reactor. In conclusion, evidence of allergy, particularly allergy to thiopental as a possible basis for the reactions, was obtained in greater than 50% of the patients who were investigated. No allergy to succinylcholine was found.

Psychological features of subjects with idiopathic environmental intolerance

OBJECTIVES Idiopathic environmental intolerance (IEI) is associated with unexplained symptoms attributed to non-noxious levels of environmental substances. Clinically, some of the symptoms of IEI overlap with those of panic disorder (PD). We have recently reported a link between IEI and panic responses to a single inhalation of 35% carbon dioxide (CO(2)), a reliable panic induction challenge. This study assessed depression, stress, anxiety, and agoraphobic symptoms among IEI subjects from our previous study versus healthy controls. METHODS Thirty-six IEI and 37 control subjects with no preexisting psychiatric history were compared on self-report psychological questionnaires. RESULTS IEI subjects scored significantly higher than controls on the Agoraphobic Cognitions Questionnaire (ACQ), Depression Anxiety Stress Scales (DASS), and Mobility Inventory for Agoraphobia (MI) (Students t, P<.05). CONCLUSIONS IEI subjects represent a group with morbidity significantly higher than a control population but less than what would be expected for a clinical psychiatric population.

Allergy to supplemental lactase enzyme

unmeasurable) and unconsciousness within a few minutes after administration of the drug. There were no signs of respiratory failure at that moment. After another few minutes, asystole developed. The patient was successfully resuscitated, and hemodynamics were monitored in the intensive care unit for 1 day. After 1 day, he recovered without further complications. There were no sign s of either acute myocardial infarction or pulmonary embolism. No tryptase level was measured. Several weeks after discharge, cutaneous tests were performed. A prick test with omeprazole (4 mg/ml) resulted in a wheal and erythema at the test site within 10 minutes, comparable with the results of a histamine prick test. Omeprazole prick tests in control subjects did not cause a reaction.

Adverse cutaneous reactions associated with fluoxetine strategy for reintroduction of this drug in selected patients.

Four patients treated with fluoxetine alone developed generalized urticaria. One also suffered polyarthritis. These reactions subsided when fluoxetine was stopped. After 6-12 months, because of progressive psychiatric problems, fluoxetine was reintroduced using a desensitization protocol. In each case this was well tolerated, and fluoxetine has been continued without adverse affects for 3-10 months.