Multiple Chemical Sensitivity/Idiopathic Environmental Intolerance: A Practical Approach to Diagnosis and Management.

Patients with multiple chemical sensitivity, now called idiopathic environmental intolerance, frequently present to clinical immunologists and allergists for diagnosis and treatment. Patients report a plethora of respiratory and multisystem problems attributed to a wide variety of unrelated, otherwise non-noxious, triggers. They may go to extreme, often seemingly bizarre lengths to avoid contact with everyday exposures and may become housebound, unable to work or function socially. Often beginning with exposure to odors, triggers can multiply to involve foods, clothing, medications, and even electromagnetic radiation. The condition cannot be explained by IgE-mediated or other immune processes, and clinical immunologists and allergists may feel unprepared to care for such patients. In this article, a paradigm to understand the probable mechanisms underlying this condition and a practical approach to diagnosis and management will be presented.

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.

Antenatal risk factors for peanut allergy in children.

BACKGROUND: Prenatal factors may contribute to the development of peanut allergy. We evaluated the risk of childhood peanut allergy in association with pregnancy exposure to Rh immune globulin, folic acid and ingestion of peanut-containing foods. METHODS: We conducted a web-based case-control survey using the Anaphylaxis Canada Registry, a pre-existing database of persons with a history of anaphylaxis. A total of 1300 case children with reported peanut allergy were compared to 113 control children with shellfish allergy. All were evaluated for maternal exposure in pregnancy to Rh immune globulin and folic acid tablet supplements, as well as maternal avoidance of dietary peanut intake in pregnancy. RESULTS: Receipt of Rh immune globulin in pregnancy was not associated with a higher risk of peanut allergy (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.51 to 1.45), nor was initiation of folic acid tablet supplements before or after conception (OR 0.53, 95% CI 0.19 to 1.48). Complete avoidance of peanut-containing products in pregnancy was associated with a non-significantly lower risk of peanut allergy (OR 0.53, 95% CI 0.27 to 1.03). CONCLUSION: The risk of childhood peanut allergy was not modified by the following common maternal exposures in pregnancy: Rh immune globulin, folic acid or peanut-containing foods. CLINICAL IMPLICATIONS: Rh immune globulin, folic acid supplement use and peanut avoidance in pregnancy have yet to be proven to modulate the risk of childhood anaphylaxis to peanuts. CAPSULE SUMMARY: Identification of prenatal factors that contribute to peanut allergy might allow for prevention of this life-threatening condition. This article explores the role of three such factors.

Hereditary Angioedema in Pregnancy.

IMPORTANCE: Hereditary angioedema is a rare disease of potentially life-threatening attacks of angioedema that can affect patients of all ages, including women of childbearing age. Pregnancy can affect the course of the disease and the choice of treatment used. It is important for the care providers to recognize this disease and understand its mechanism in order to provide appropriate care for the patients. OBJECTIVE: The goal of this article is to provide an overview of hereditary angioedema and guideline for management of pregnant patients with hereditary angioedema. EVIDENCE ACQUISITION: A search of the available English language literature was performed on PubMed and Ovid MEDLINE using the key words hereditary angioedema and pregnancy. Additional articles were selected from the reference lists of the reviewed articles. RESULTS: The data for hereditary angioedema in pregnant patients come from observational studies, case reports, retrospective reviews, and questionnaires. The course of hereditary angioedema can be variable between different patients and pregnancies. Plasma-derived C1 inhibitor concentrate is both safe and effective as treatment for attacks and as preventive therapy in pregnancy. With proper recognition, understanding of the disease, and appropriate medical management, most patients will undergo successful pregnancy and delivery. CONCLUSIONS AND RELEVANCE: Clinicians should maintain high suspicion for this disease when patients present with recurrent episodes of angioedema without urticaria or severe abdominal pains of unclear etiology. Treatment plans during pregnancy and delivery should be individualized, and the patient's care should be shared by a clinician experienced in the management of this disease.

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.

2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema.

BACKGROUND: We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) and updated this as Hereditary angioedema: a current state-of-the-art review: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. OBJECTIVE: To update the International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema (circa 2010). METHODS: The Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d'angioédème héréditaire (RCAH) http://www.haecanada.com and cosponsors University of Calgary and the Canadian Society of Allergy and Clinical Immunology (with an unrestricted educational grant from CSL Behring) held our third Conference May 15th to 16th, 2010 in Toronto Canada to update our consensus approach. The Consensus document was reviewed at the meeting and then circulated for review. RESULTS: This manuscript is the 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema that resulted from that conference. CONCLUSIONS: Consensus approach is only an interim guide to a complex disorder such as HAE and should be replaced as soon as possible with large phase III and IV clinical trials, meta analyses, and using data base registry validation of approaches including quality of life and cost benefit analyses, followed by large head-to-head clinical trials and then evidence-based guidelines and standards for HAE disease management.

Successful Treatment of Long Standing Complex Regional Pain Syndrome with Hyperbaric Oxygen Therapy.

Complex regional pain syndrome (CRPS) is a devastating posttraumatic neuroinflammatory condition with both autoinflammatory and autoimmune features, characterized by unrelenting severe pain and disability, with the majority of affected patients being unable to function socially or vocationally. Remission is more likely in children than adults, and if treatment is started early. Once established, there are no universally effective treatments, and these are desperately needed. A single limb is often involved, but there can be multi-limb spread, and systemic autonomic manifestations. We describe a case of long-standing CRPS with multi-limb spread and systemic autonomic features, controlled only with very high dose oral corticosteroids, which led to several complications. Multiple other treatment modalities failed or were insufficient to control the CRPS and allow tapering of the corticosteroids, but the patient had a dramatic response to hyperbaric oxygen therapy (HBOT), allowing a reduction in prednisone dose to just over the physiologic range. When symptoms started to increase several months later, a second course of HBOT treatments allowed reduction in prednisone dose into the physiologic range while still controlling CRPS symptoms. This case is unique in that it shows that HBOT can be effective in long-standing CRPS, both initially, and for subsequent flares, and adds to the evidence supporting HBOT as a potential treatment for this condition. Graphical Abstract HBOT effect on prednisone dose for symptom control.

Measurement of Bradykinin Formation and Degradation in Blood Plasma: Relevance for Acquired Angioedema Associated With Angiotensin Converting Enzyme Inhibition and for Hereditary Angioedema Due to Factor XII or Plasminogen Gene Variants.

Bradykinin (BK)-mediated angioedema (AE) states are rare acquired or hereditary conditions involving localized edema of the subcutaneous and submucosal tissues. Citrated plasma from healthy volunteers or patients with hereditary angioedema (HAE) with normal level of C1-inhibitor (C1-INH) was used to investigate pathways of BK formation and breakdown relevant to AE physiopathology. The half-life of BK (100 nM) added to normal plasma was 34 s, a value that was increased ~12-fold when the angiotensin converting enzyme (ACE) inhibitor enalaprilat (130 nM) was added (enzyme immunoassay measurements). The BK half-life was similarly increased ~5-fold following 2 daily oral doses of enalapril maleate in healthy volunteers, finding of possible relevance for the most common form of drug-associated AE. We also addressed the kinetics of immunoreactive BK (iBK) formation and decline, spontaneous or under three standardized stimuli: tissue kallikrein (KLK-1), the particulate material Kontact-APTT™ and tissue plasminogen activator (tPA). Relative to controls, iBK production was rapid (10-20 min) and very intense in response to tPA in plasma of female heterozygotes for variants in gene F12 coding for factor XII (FXII) (p.Thr328Lys, 9 patients; p.Thr328Arg, one). An increased response to Kontact-APTT™ and an early tPA-induced cleavage of anomalous FXII (immunoblots) were also observed. Biotechnological inhibitors showed that the early response to tPA was dependent on plasmin, FXIIa and plasma kallikrein. Results from post-menopausal and pre-menopausal women with HAE-FXII were indistinguishable. The iBK production profiles in seven patients with the plasminogen p.Lys330Glu variant (HAE-PLG) did not significantly differ from those of controls, except for an unexpected, rapid and lanadelumab-resistant potentiation of KLK-1 effect. This enzyme did not cleave plasminogen or factor XII, suggesting a possible idiosyncratic interaction of the plasminogen pathogenic variant with KLK-1 activity. KLK-1 abounds in salivary glands and human saliva, hypothetically correlating with the clinical presentation of HAE-PLG that includes the swelling of the tongue, lips and contiguous throat tissues. Samples from HAE patients with normal C1-INH levels and F12 gene did not produce excessive iBK in response to stimuli. The ex vivo approach provides physiopathological insight into AE states and supports the heterogeneous physiopathology of HAE with normal C1-INH.

Development of the Hereditary Angioedema Rapid Triage Tool.

BACKGROUND: Patients with hereditary angioedema (HAE) present to the emergency department (ED), where their symptoms are often incorrectly attributed to common allergic and gastrointestinal conditions, resulting in major delays in diagnosis and treatment. OBJECTIVE: To develop a rapid triage HAE (Hereditary AngioEdema Rapid Triage [HAE-RT]) tool for ED settings. METHODS: A mixed-methods approach was used in 3 phases: Phase 1: A literature review on the current management of patients with HAE in the ED. Phase 2: A Delphi study with HAE specialists (N = 9) and Patient Advocacy Group Members (N = 3) to reach consensus on the predictor variables (PVs) to be included in the HAE-RT tool. Phase 3: A retrospective chart review to assess the performance of the PVs for HAE. RESULTS: The literature review informed the final list of PVs included in the HAE-RT prototype. Nine experts participated in the Delphi study. Of 8 identified HAE-specific PVs, 3 reached consensus: (1) absence of urticaria, (2) recurrent abdominal pain/swelling, and (3) lack of response to allergic-directed therapy. The retrospective study included 107 patients (N = 66 with HAE; N = 41 non-HAE). Patients with HAE were more likely to have a family history of HAE (71%; P < .0001), previous recurrent angioedema (96%; P < .002), and previous recurrent abdominal pain (77%; P < .0001), and only 6% responded to allergy treatments (P < .0001). The HAE-RT tool had 98% sensitivity and specificity. CONCLUSIONS: Expert consensus led to the identification and prioritization of variables that when incorporated into an HAE-RT tool were associated with a high level of sensitivity and specificity when applied to known patients.

Correction to: The International/Canadian Hereditary Angioedema Guideline.

[This corrects the article DOI: 10.1186/s13223-019-0376-8.].

The International/Canadian Hereditary Angioedema Guideline.

This is an update to the 2014 Canadian Hereditary Angioedema Guideline with an expanded scope to include the management of hereditary angioedema (HAE) patients worldwide. It is a collaboration of Canadian and international HAE experts and patient groups led by the Canadian Hereditary Angioedema Network. The objective of this guideline is to provide evidence-based recommendations, using the GRADE system, for the management of patients 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. New to the 2019 version of this guideline are sections covering the diagnosis and recommended therapies for acute treatment in HAE patients with normal C1-INH, as well as sections on pregnant and paediatric patients, patient associations and an HAE registry. Hereditary angioedema results in 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, as in many countries, continues to be neither optimal nor uniform. It lags behind some other countries where there are more organized models for HAE management, and greater availability of additional licensed therapeutic options. It is anticipated that providing this guideline to caregivers, policy makers, patients, and advocates will not only optimize the management of HAE, but also promote the importance of individualized care. 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 and intensive care physicians, primary care physicians, gastroenterologists, dentists, otolaryngologists, paediatricians, and gynaecologists 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.

Diagnostic accuracy of skin-prick testing for allergic rhinitis: a systematic review and meta-analysis.

BACKGROUND: Allergic rhinitis is the most common form of allergy worldwide. The accuracy of skin testing for allergic rhinitis is still debated. Our primary objective was to evaluate the diagnostic accuracy of skin-prick testing for allergic rhinitis using the nasal provocation as the reference standard. We also evaluated the diagnostic accuracy of intradermal testing as a secondary objective. METHODS: We searched EBM Reviews from 2005 to March 2015; Embase from 1980 to March 2015; and Ovid MEDLINE(R) from 1946 to until March 2015. We included any study with at least 10 subjects including children. We excluded non-English studies. We performed data extraction and quality assessment using the QUADAS-2 tool. RESULTS: We meta-analysed seven studies assessing the accuracy of skin-prick testing using the bivariate random-effects model, including a total of 430 patients. The pooled estimate for sensitivity and specificity for skin-prick testing was 85 and 77 % respectively. We did not pool results for intradermal testing due to few number of studies (n = 4), each with very small sample size. Of these, two evaluated the accuracy of intradermal testing in confirming skin-prick testing results, with sensitivity ranging from 27 to 50 % and specificity ranging from 60 to 100 %. The other two evaluated the accuracy of intradermal testing as a stand-alone test for diagnosing allergic rhinitis with sensitivity ranging from 60 to 79 % and specificity ranging from 68 to 69 %. CONCLUSIONS: Findings from this review suggest that skin-prick testing is accurate in discriminating subjects with or without allergic rhinitis.

Hydrochlorothiazide-induced noncardiogenic pulmonary edema: an underrecognized yet serious adverse drug reaction.

Noncardiogenic pulmonary edema is a rare but potentially life-threatening complication of hydrochlorothiazide therapy. We describe three patients who developed this serious adverse reaction. A 64-year-old woman developed dypsnea and hypotension within 60 minutes of taking a single dose of hydrochlorothiazide 25 mg. She was admitted to the critical care unit with acute respiratory failure and subsequent multiple-organ dysfunction. The second patient was a 56-year-old woman who experienced sudden onset of shortness of breath that developed 10 minutes after taking a single dose of hydrochlorothiazide 25 mg. The third was a 59-year-old woman who developed sudden onset of shortness of breath, nausea, vomiting, and diarrhea after her first dose of hydrochlorothiazide-triamterene. All three women had a history of a similar, albeit minor, reaction to a thiazide diuretic. Review of the literature identified 36 additional cases of noncardiogenic pulmonary edema after thiazide use. The patients developed symptoms 10-150 minutes after ingestion of hydrochlorothiazide or another thiazide. Symptoms can occur on first exposure to the drug or in patients taking the drug intermittently. Of interest, 90% of documented cases occurred in women. With the increasing use of thiazide diuretics in the treatment of hypertension, clinicians need to be aware of the possible association of these drugs with the development of noncardiogenic pulmonary edema.

Responses to panic induction procedures in subjects with multiple chemical sensitivity/idiopathic environmental intolerance: understanding the relationship with panic disorder.

Idiopathic environmental intolerance (IEI), also known as multiple chemical sensitivity, is a clinical description for a cluster of symptoms of unknown etiology that have been attributed by patients to multiple environmental exposures when other medical explanations have been excluded. Because allergy has not been clearly demonstrated and current toxicological paradigms for exposure-symptom relationships do not readily accommodate IEI, psychogenic theories have been the focus of a number of investigations. A significantly higher lifetime prevalence of major depression, mood disorders, anxiety disorders, and somatization disorder has been reported among patients with environmental illness compared with that in controls. Symptoms often include anxiety, lightheadedness, impaired mentation, poor coordination, breathlessness (without wheezing), tremor, and abdominal discomfort. Responses to intravenous sodium lactate challenge or single-breath inhalation of 35% carbon dioxide versus a similar breath inhalation of clean air have shown a greater frequency of panic responses in subjects with IEI than in control subjects, although such responses did not occur in all subjects. Preliminary genetic findings suggest an increased frequency of a common genotype with panic disorder patients. The panic responses in a significant proportion of IEI patients opens a therapeutic window of opportunity. Patients in whom panic responses may at least be a contributing factor to their symptoms might be responsive to intervention with psychotherapy to enable their desensitization or deconditioning of responses to odors and other triggers, and/or may be helped by anxiolytic medications, relaxation training, and counseling for stress management.

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.

Idiopathic environmental intolerance: Part 2: A causation analysis applying Bradford Hill's criteria to the psychogenic theory.

Toxicogenic and psychogenic theories have been proposed to explain idiopathic environmental intolerance (IEI). Part 2 of this article is an evidence-based causality analysis of the psychogenic theory using an extended version of Bradford Hill's criteria. The psychogenic theory meets all of the criteria directly or indirectly and is characterised by a progressive research programme including double-blind, placebo-controlled provocation challenge studies. We conclude that IEI is a belief characterised by an overvalued idea of toxic attribution of symptoms and disability, fulfilling criteria for a somatoform disorder and a functional somatic syndrome. A neurobiological diathesis similar to anxiety, specifically panic disorder, is a neurobiologically plausible mechanism to explain triggered reactions to ambient doses of environmental agents, real or perceived. In addition, there is a cognitively mediated fear response mechanism characterised by vigilance for perceived exposures and bodily sensations that are subsequently amplified in the process of learned sensitivity. Implications for the assessment and treatment of patients are presented.