Publications by authors named "Christine McCusker"

58 Publications

Fruit-Induced Anaphylaxis: Clinical Presentation and Management.

J Allergy Clin Immunol Pract 2021 Mar 13. Epub 2021 Mar 13.

Division of Allergy and Clinical Immunology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada.

Background: Data are sparse regarding the clinical characteristics and management of fruit-induced anaphylaxis.

Objective: To assess clinical characteristics and management of patients with fruit-induced anaphylaxis and determine factors associated with severe reactions and epinephrine use.

Methods: Over 9 years, children and adults presenting with anaphylaxis to seven emergency departments in four Canadian provinces and patients requiring emergency medical services in Outaouais, Quebec were recruited as part of the Cross-Canada Anaphylaxis Registry. A standardized form documenting symptoms, triggers, and management was collected. Multivariate logistic regression was used to identify factors associated with severe reactions and epinephrine treatment in the pre-hospital setting.

Results: We recruited 250 patients with fruit-induced anaphylaxis, median age 10.2 years (interquartile range, 3.6-23.4 years); 48.8% were male. The most common fruit triggers were kiwi (15.6%), banana (10.8%), and mango (9.2%). Twenty-three patients reported having eczema (9.3%). Epinephrine use was low in both the pre-hospital setting and the emergency department (28.4% and 40.8%, respectively). Severe reactions to fruit were more likely to occur in spring and among those with eczema (adjusted odds ratio [aOR] = 1.12, 95% confidence interval [CI], 1.03-1.23; and 1.17, 95% CI, 1.03-1.34, respectively). Patients with moderate and severe reactions (aOR = 1.23; 95% CI, 1.06-1.43) and those with a known food allergy (aOR = 1.38; 95% CI, 1.24-1.54) were more likely to be treated with epinephrine in the pre-hospital setting.

Conclusions: Severe anaphylaxis to fruit is more frequent in spring. Cross-reactivity to pollens is a potential explanation that should be evaluated further.
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http://dx.doi.org/10.1016/j.jaip.2021.02.055DOI Listing
March 2021

Quality of life in patients with hereditary angioedema in Canada.

Ann Allergy Asthma Immunol 2021 04 13;126(4):394-400.e3. Epub 2021 Jan 13.

Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Clinical Immunology and Allergy, Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

Background: Hereditary angioedema (HAE) is associated with decreased quality of life (QoL), which has typically been measured using a generic non-disease-specific questionnaire.

Objective: We aimed to assess the QoL in patients with HAE type I and II in Canada using a previously validated HAE-specific questionnaire.

Methods: An online questionnaire was sent to the members of two Canadian HAE patient groups to collect data on demographics, HAE clinical course, and QoL scores. All patients 18 years of age or older with HAE type I or II were eligible. The impact of the available clinical factors on the QoL scores was evaluated. Multiple linear regression was performed using clinically relevant factors to predict HAE QoL outcome.

Results: Among the 72 patients in the study, the mean total HAE QoL score was 102 (±23) (SD) on a scale of 25 to 135, with higher scores indicating better QoL. Although the total QoL scores correlated positively with patients' level of satisfaction and perceived control (P < .001 for both), it correlated negatively with the number of acute attacks (P = .03). Yet, the types of treatment did not have an impact on the QoL. Predictors, including sex, comorbidities, and the number of attacks, only explained 12% of the variance in the total QoL scores.

Conclusion: HAE continues to impair QoL in Canadian patients despite receiving recommended treatment. Although the frequency of attacks affects QoL, patients' experience with their HAE care also affects QoL substantially. The study highlights the importance of considering patients' experience with their HAE care as physicians develop an appropriate management plan.
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http://dx.doi.org/10.1016/j.anai.2021.01.002DOI Listing
April 2021

Specific IgE antibody levels during and after food-induced anaphylaxis.

Clin Exp Allergy 2021 Feb 9;51(2):364-368. Epub 2020 Dec 9.

Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, McGill University, Montreal, QC, Canada.

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http://dx.doi.org/10.1111/cea.13796DOI Listing
February 2021

Differentiating Between β-Lactam-Induced Serum Sickness-Like Reactions and Viral Exanthem in Children Using a Graded Oral Challenge.

J Allergy Clin Immunol Pract 2021 Feb 6;9(2):916-921. Epub 2020 Sep 6.

Department of Pediatrics, Division of Allergy and Clinical Immunology, Montreal Children's Hospital, Montreal, Quebec, Canada.

Background: Serum sickness-like reactions (SSLRs) are defined by the presence of rash (primarily urticaria) and joint complaints (arthralgia/arthritis) that are believed to occur due to a non-IgE-mediated response to medications. However, similar reactions can occur due to viral infections, and it can be difficult to distinguish between the two. This may lead to unnecessary avoidance of the culprit antibiotic.

Objective: We aimed to evaluate children presenting with suspected SSLRs through a graded oral challenge (GOC).

Methods: All children referred to the Montreal Children's Hospital for potential antibiotic allergy (β-lactam or other antibiotics) and a clinical presentation compatible with SSLR were recruited for the study between March 2013 and February 2020. A standardized survey with questions on treatment, symptoms, and associated factors was completed, and a GOC (10% and subsequently 90% of the oral antibiotic dose) was conducted. Patients with a negative GOC were contacted annually to query on subsequent antibiotic use.

Results: Among 75 patients presenting with suspected SSLRs, the median age was 2.0 years and 46.7% were males. Most reactions were attributed to amoxicillin. Among the 75 patients, 2.7% reacted immediately (within 1 hour) to a GOC and 4.0% had a nonimmediate reaction. Of the 43 patients successfully contacted, 20 reported subsequent culprit antibiotic use of whom 25.0% had a subsequent mild reaction (macular/papular rash).

Conclusions: This is the first and largest pediatric study to assess SSLR using a GOC. Our findings suggest that using a GOC is safe and appropriate for differentiating between β-lactam-induced SSLR and viral exanthem in this population.
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http://dx.doi.org/10.1016/j.jaip.2020.08.047DOI Listing
February 2021

A novel pathogenic SH2D1A mutation for X-linked lymphoproliferative syndrome type 1.

Clin Immunol 2020 Oct 10;219:108569. Epub 2020 Aug 10.

Division of Allergy Immunology and Dermatology, Department of Pediatrics, McGill University Health Centre, Montreal, Quebec, Canada.

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http://dx.doi.org/10.1016/j.clim.2020.108569DOI Listing
October 2020

COVID-19 and comorbidities: a systematic review and meta-analysis.

Postgrad Med 2020 Nov 14;132(8):749-755. Epub 2020 Jul 14.

Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, McGill University Health Centre , Montreal, Quebec, Canada.

SARS-CoV-2 has caused a worldwide pandemic that began with an outbreak of pneumonia cases in the Hubei province of China. Knowledge of those most at risk is integral for treatment, guideline implementation, and resource allocation. We conducted a systematic review and meta-analysis to evaluate comorbidities associated with severe and fatal cases of COVID-19. A search was conducted on PubMed and EmBase on 20 April 2020. Pooled estimates were collected using a random-effects model. Thirty-three studies were included in the systematic review and twenty-two in the meta-analysis. Of the total cases 40.80% (95%CI: 35.49%, 46.11%) had comorbidities, while fatal cases had 74.37% (95%CI: 55.78%, 86.97%). Hypertension was more prevalent in severe [47.65% (95%CI: 35.04%, 60.26%)] and fatal [47.90% (95%CI: 40.33%, 55.48%)] cases compared to total cases [14.34% (95%CI: 6.60%, 28.42%)]. Diabetes was more prevalent among fatal cases [24.89% (95%CI: 18.80%, 32.16%)] compared to total cases [9.65% (95%CI: 6.83%, 13.48%)]. Respiratory diseases had a higher prevalence in fatal cases [10.89% (95%CI: 7.57%, 15.43%)] in comparison to total cases [3.65% (95%CI: 2.16%, 6.1%)]. Studies assessing the mechanisms accounting for the associations between severe cases and hypertension, diabetes, and respiratory diseases are crucial in understanding this new disease, managing patients at risk, and developing policies and guidelines that will reduce future risk of severe COVID-19 disease.
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http://dx.doi.org/10.1080/00325481.2020.1786964DOI Listing
November 2020

Anaphylaxis as a presenting symptom of food allergy in children with no known food allergy.

J Allergy Clin Immunol Pract 2020 09 26;8(8):2811-2813.e2. Epub 2020 Apr 26.

Division of Allergy and Clinical Immunology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada.

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http://dx.doi.org/10.1016/j.jaip.2020.04.033DOI Listing
September 2020

The International/Canadian Hereditary Angioedema Guideline.

Allergy Asthma Clin Immunol 2019 25;15:72. Epub 2019 Nov 25.

39Department of Internal Medicine, Queen's University, Kingston, ON Canada.

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.
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http://dx.doi.org/10.1186/s13223-019-0376-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878678PMC
November 2019

The pathogenesis and management of renal scarring in children with vesicoureteric reflux and pyelonephritis.

Pediatr Nephrol 2020 03 7;35(3):349-357. Epub 2019 Mar 7.

Montreal Childrens Hospital, Montreal, Quebec, Canada.

Bacterial urinary tract infections (UTIs) are one of the most common reasons for children to be admitted to hospital. Bacteria infect and invade the bladder (the lower urinary tract) and if the infection disseminates to the upper urinary tract, significant inflammation in the kidneys may arise. Inflammation is a double-edged sword: it is needed to clear bacteria, but if excessive, kidney tissue is injured. During injury, nephrons are destroyed and replaced with deposition of extracellular matrix and a renal scar. In this review, we explore the pathogenesis of UTIs and discuss the risk factors that result in dissemination of bladder infection to the kidneys. Three major risk factors predispose to kidney infections: the presence of vesicoureteric reflux, the presence of bladder and bowel dysfunction, and defects in the ability of the host immune response to clear bacteria. In this review, we will discuss these factors, their relationship to renal scarring, and potential treatments that might be beneficial to prevent renal scar formation in children.
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http://dx.doi.org/10.1007/s00467-018-4187-9DOI Listing
March 2020

A Comprehensive Review on Kiwifruit Allergy: Pathogenesis, Diagnosis, Management, and Potential Modification of Allergens Through Processing.

Compr Rev Food Sci Food Saf 2019 Mar 29;18(2):500-513. Epub 2019 Jan 29.

Dept. of Bioresource Engineering, Faculty of Agricultural and Environmental Sciences, McGill Univ., Sainte-Anne-de-Bellevue, Quebec, Canada.

Kiwifruit is rich in bioactive components including dietary fibers, carbohydrates, natural sugars, vitamins, minerals, omega-3 fatty acids, and antioxidants. These components are beneficial to boost the human immune system and prevent cancer and heart diseases. However, kiwifruit is emerging as one of the most common elicitors of food allergies worldwide. Kiwifruit allergy results from an abnormal immune response to kiwifruit proteins and occur after consuming this fruit. Symptoms range from the oral allergy syndrome (OAS) to the life-threatening anaphylaxis. Thirteen different allergens have been identified in green kiwifruit and, among these allergens, Act d 1, Act d 2, Act d 8, Act d 11, and Act d 12 are defined as the "major allergens." Act d 1 and Act d 2 are ripening-related allergens and are found in abundance in fully ripe kiwifruit. Structures of several kiwifruit allergens may be altered under high temperatures or strong acidic conditions. This review discusses the pathogenesis, clinical features, and diagnosis of kiwifruit allergy and evaluates food processing methods including thermal, ultrasound, and chemical processing which may be used to reduce the allergenicity of kiwifruit. Management and medical treatments for kiwifruit allergy are also summarized.
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http://dx.doi.org/10.1111/1541-4337.12426DOI Listing
March 2019

Anaphylaxis to patent blue dye in a 17-year-old boy.

BMJ Case Rep 2019 Jan 22;12(1). Epub 2019 Jan 22.

Division of Allergy Immunology and Dermatology, Department of Paediatrics, McGill University Health Centre, Montreal, Quebec, Canada.

Patent blue V dye (PBV) is frequently used as a perioperative drug for lymphangiography, as well as a food additive. Hypersensitivity to PBV is poorly documented in adults and had not been previously described in children. The diagnosis of PBV allergy depends on corroboration of history consistent with an IgE-mediated reaction and confirmatory skin tests. We present in this paper a paediatric case of PBV anaphylaxis and of biphasic reaction that exemplifies the challenges involved in diagnosing and managing this rare but potentially life-threatening allergic reaction.
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http://dx.doi.org/10.1136/bcr-2018-226191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347920PMC
January 2019

Primary immunodeficiency.

Allergy Asthma Clin Immunol 2018 12;14(Suppl 2):61. Epub 2018 Sep 12.

4University of Manitoba, Winnipeg, MB Canada.

Primary immunodeficiency disorder (PID) refers to a large heterogeneous group of disorders that result from defects in immune system development and/or function. PIDs are broadly classified as disorders of adaptive immunity (i.e., T cell, B-cell or combined immunodeficiencies) or of innate immunity (e.g., phagocyte and complement disorders). Although the clinical manifestations of PIDs are highly variable, many disorders involve an increased susceptibility to infection. Early consultation with a clinical immunologist is essential, as timely diagnosis and treatment are imperative for preventing significant disease-associated morbidity. PIDs should be suspected in patients with: recurrent sinus or ear infections or pneumonias within a 1 year period; failure to thrive; poor response to prolonged use of antibiotics; persistent thrush or skin abscesses; or a family history of PID. Patients with multiple autoimmune diseases should also be evaluated. Diagnostic testing often involves lymphocyte proliferation assays, flow cytometry, measurement of serum immunoglobulin (Ig) levels, assessment of serum specific antibody titers in response to vaccine antigens, neutrophil function assays, stimulation assays for cytokine responses, and complement studies. The treatment of PIDs is complex and generally requires both supportive and definitive strategies. Ig replacement therapy is the mainstay of therapy for B-cell disorders, and is also an important supportive treatment for many patients with combined immunodeficiency disorders. The disorders affecting the activity of the T-cell arm of the adaptive system, such as severe combined immunodeficiency, require immune reconstitution as soon as possible. The treatment of innate immunodeficiency disorders varies depending on the type of defect, but may involve antifungal and antibiotic prophylaxis, cytokine replacement, vaccinations and bone marrow transplantation. This article provides an overview of the major categories of PIDs and strategies for the appropriate diagnosis and management of these rare disorders.
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http://dx.doi.org/10.1186/s13223-018-0290-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157160PMC
September 2018

Modulation of the Interleukin-21 Pathway with Interleukin-4 Distinguishes Common Variable Immunodeficiency Patients with More Non-infectious Clinical Complications.

J Clin Immunol 2018 01 4;38(1):45-55. Epub 2017 Nov 4.

Division of Allergy and Immunology, Department of Paediatrics, McGill University Health Centre, Montreal, Quebec, Canada.

Purpose: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and clinical manifestations such as infections, autoimmunity, and malignancy. We sought to determine if responsiveness to interleukin-21 (IL-21), a key cytokine for B cell differentiation, correlates with distinct clinical phenotypes in CVID.

Methods: CVID subjects were recruited through the Canadian Primary Immunodeficiency Evaluative Survey registry. Peripheral blood mononuclear cells were cultured with anti-CD40 ± interferon-gamma, interleukin-4 (IL-4), IL-21, and/or IL-4+IL-21. B cell subpopulations and IgG production were determined at baseline and day 7 by flow cytometry and ELISA. Clinical complications were compared using contingency tables.

Results: CVID subjects exhibited decreased CD27 B cells and IgG production after 7 days of stimulation with anti-CD40+IL-21 (p < 0.05). In a subset of subjects [CVID responders (R)], the addition of IL-4 led to significant increases in CD27 B cells and IgG (p < 0.05). In CVID non-responders (NR), CD27 B cells and IgG remained lower despite the addition of IL-4. CVID NR experienced significantly more non-infectious clinical complications of CVID than R [OR 8.8, 95% confidence interval (CI) 1.6 to 48.13]. Previous studies reported that CVID subjects with ≤ 2% class-switched memory B cells were more at risk of these complications, but no significant association was found among this cohort of subjects [OR 3.5, CI 0.9 to 13.3]. In fact, 34.6% of CVID NR had > 2% class-switched memory B cells at baseline.

Conclusions: The IL-4 and IL-21 in vitro assays distinguish two groups of CVID subjects and can be used with baseline B cell subpopulation phenotyping to better identify patients experiencing more vs. fewer clinical non-infectious complications and potentially to modulate therapy.
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http://dx.doi.org/10.1007/s10875-017-0452-0DOI Listing
January 2018

Morpholino-based correction of hypomorphic ZAP70 mutation in an adult with combined immunodeficiency.

J Allergy Clin Immunol 2017 05 17;139(5):1688-1692.e10. Epub 2017 Feb 17.

Infectious Disease Susceptibility Program, McGill University Health Centre (MUHC) and Research Institute-MUHC (RI-MUHC), Montreal, Quebec, Canada; Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2017.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7126384PMC
May 2017

-first do no harm. And then feed peanut.

Allergy Asthma Clin Immunol 2017 8;13. Epub 2017 Feb 8.

Dalhousie University, 503-5657 Spring Garden Road, Halifax, NS B3J 3R4 Canada.

The -- were developed to build on previous food allergy guidelines after several key studies demonstrated the benefit of early introduction of allergenic foods. These landmark studies including the Learning Early about Peanut (LEAP), LEAP-On and Enquiring about Tolerance trials created a paradigm shift in food allergy prevention. The "take home" messages of this guideline include that peanut should be introduced early in the first year of life, and for the majority of infants, peanut can be introduced at home. The only group of infants for which medical assessment is recommended is those with severe eczema, egg allergy or both. Here we summarize the Guideline recommendations, endorsed by the Canadian Society of Allergy and Clinical Immunology, and highlight important aspects relevant to Canadian practitioners.
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http://dx.doi.org/10.1186/s13223-017-0180-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299733PMC
February 2017

T-cell receptor phenotype pattern in atopic children using commercial fluorescently labeled antibodies against 21 human class-specific v segments for the tcrβ chain (vβ) of peripheral blood: a cross sectional study.

Allergy Asthma Clin Immunol 2016 2;12:10. Epub 2016 Mar 2.

Division of Allergy and Clinical Immunology, Department of Pediatrics, Montreal Children's Hospital, McGill University, 1001 Boulevard Décarie, Room A 02.2227, Montréal, QC H4A 3J1 Canada.

Background: T-cell receptor (TCR) repertoire development is an integral part of the adaptive immune response. T-cell activation requires recognition of appropriately processed antigens by the TCR. Development of a diverse repertoire of TCRs is therefore essential to ensure adequate protection from potential threats. The majority of T-cells in peripheral blood have TCRs composed of an alpha and a beta chain. At the DNA level, the TCR genes are formed through directed recombination from germline sequences-the so-called VDJ recombination [variable (V) joining (J) diversity (D) gene segments] which results in variations in the repertoire. The most variable part of TCRs is the Vβ region (VβTCR), which has multiple V segment families that can be quantitatively measured. However, only sparse data exists on the normal levels of the VβTCR repertoire in healthy children. We aimed to establish normal values for the VβTCR repertoire in atopic children without immunodeficiency.

Methods: Fifty-three children were recruited from food allergy, drug allergy, chronic urticaria and anaphylaxis registries and were divided into groups based on age: >0-2 years, 3-6 years, and 6-18 years. We used commercially available and fluorescently labeled antibodies against 21 human class-specific V segments of the TCRβ chain (Vβ) to study in peripheral blood the quantitative pattern of Vβ variation by flow cytometry.

Results: Children of all ages exhibited a similar pattern of TCR Vβ expression. Vβ 2 was the most commonly expressed family in all three age groups [9.5 % (95 % CI, 8.9, 10 %), 8.8 % (95 % CI, 7.4, 10.2 %) and 7.6 % (7.0, 8.3 %) respectively]. However, the percentage of Vβ 2 decreased in older children and the percentage of Vβ 1 was higher in males. TCR Vβ expression in our sample of atopic children did not differ substantially from previously published levels in non-atopic cohorts.

Conclusion: TCR Vβ diversity follows a predictable and comparable pattern in atopic and healthy non-atopic children. Establishing normal levels for healthy children with and without atopy will contribute to a better definition of Vβ receptor deviation in children with primary immunodeficiency and/or immunodysregulation conditions.
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http://dx.doi.org/10.1186/s13223-016-0115-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776431PMC
March 2016

The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1.

J Clin Immunol 2016 Jan 25;36(1):73-84. Epub 2015 Nov 25.

Center for Chronic Immunodeficiency, University Medical Center Freiburg, Engesser Straße 4, 79108, Freiburg, Germany.

Purpose: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients.

Methods: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients.

Results: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients.

Conclusion: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.
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http://dx.doi.org/10.1007/s10875-015-0214-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718942PMC
January 2016

Canadian hereditary angioedema guideline.

Allergy Asthma Clin Immunol 2014 24;10(1):50. Epub 2014 Oct 24.

Department of Medicine, McMaster University, Hamilton, Ontario Canada.

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.
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http://dx.doi.org/10.1186/1710-1492-10-50DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210625PMC
October 2014

Fatal pneumococcal meningitis in a 7-year-old girl with interleukin-1 receptor activated kinase deficiency (IRAK-4) despite prophylactic antibiotic and IgG responses to Streptococcus pneumoniae vaccines.

J Clin Immunol 2014 Apr 5;34(3):267-71. Epub 2014 Mar 5.

Department of Pediatrics, Dalhousie University, Halifax, NS, Canada.

Unlabelled: IRAK-4 deficiency causes IL-1R and TLR signaling failure, resulting in minimal clinical features despite invasive bacterial infection. We report the course of a 7-year-old IRAK-4-deficient girl presenting in the first year with multiple occult Staphylococcus aureus lymphadenitis. She was managed with antibiotic prophylaxis (sulfa/trimethoprim/PenV, then - due to neutropenia - Cefprozil), pneumococcal vaccination (PCV-7, Pneumovax23, PCV-13) and vigilance. Pneumococcal-specific IgG levels were monitored. No bacterial infections occurred on prophylaxis for 6 years after initial presentation. IgG response to pneumococcal polysaccharide was satisfactory but short-lived, requiring frequent boosting. At age 7, patient developed a morning headache and vomited once. Cefprozil was administered and re-dosed. Over 12 h, she was fatigued without other symptoms. Low fever accompanied another emesis. A few hours later she was confused, and purpuric rash appeared. Emergency physicians diagnosed sepsis/meningitis and started vancomycin-ceftriaxone. Respiratory failure and cerebellar herniation occurred <24 h after first symptoms. Blood and CSF grew Streptococcus pneumoniae type 6C resistant to second-generation cephalosporins. The patient's latest PCV-13 vaccination was 6 weeks before death, which included serotype 6A. Immunoglobulins were normal except IgG4 was increased (3.4 g/L). IgG response to vaccine antigens was satisfactory. IgG to 6A is reported to cross-react with 6C, but this was not the case here.

Conclusion: Despite antibiotic prophylaxis and repeated vaccination, even older IRAK-4-deficient patients are at high risk of rapidly fatal infection due to emergence of antibiotic resistance. These patients need early assessment at any age, bacterial culturing, alternative empiric antibiotic therapy and close observation when even vaguely unwell. Based on increasingly recognized immunological and/or clinical impairments in B cell function, and possibly other defects, long-term IgG prophylaxis in addition to antibiotics is recommended.
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http://dx.doi.org/10.1007/s10875-014-9996-4DOI Listing
April 2014

Altered T helper 17 responses in children with food allergy.

Int Arch Allergy Immunol 2013 25;162(4):318-22. Epub 2013 Oct 25.

Department of Microbiology and Immunology and FOCIS Center of Excellence, McGill University and the Research Institute of the McGill University Health Center, Montreal, Que., Canada.

Background: While a central role for the T helper (Th) 1/Th2 axis in food allergy has been established, the Th17 response in food-allergic humans has not been addressed.

Methods: Th17 responses in 18 peanut-allergic children, who were also allergic to at least one additional food allergen, were assessed relative to 15 age-matched healthy controls. To account for the atopy background in the allergic children, 7 atopic, but not food-allergic, individuals and their age-matched controls were included in this study. PBMCs were analyzed by flow cytometry ex vivo or were stimulated in vitro with peanut allergens, gliadin, or tetanus toxoid followed by analysis of proliferation and cytokine production in antigen-responsive cells.

Results: We observed a significantly lower interleukin (IL) 17 production in CD4+ T cells of food-allergic individuals ex vivo (p < 0.02). In vitro, we found that IL-17 production in CD4+ T cells in response to all antigens tested was significantly impaired in food-allergic subjects compared to healthy controls (Ara: p < 0.005; gliadin: p < 0.004; TT: p < 0.03). No significant differences were observed between atopic and nonatopic individuals with no food allergy.

Conclusion: Our results thus reveal a systemic, non-allergen-specific defect in Th17 responses to antigen stimulation in food allergic individuals, suggesting a role for Th17 cells in the control of food allergy and implicating IL-17 as a potential biomarker for tolerance to food antigens.
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http://dx.doi.org/10.1159/000354028DOI Listing
February 2014

Autoimmune hemolytic anemia in a teenager: a wolf in sheep's clothing.

Eur J Haematol 2013 Sep 28;91(3):262-4. Epub 2013 Jun 28.

Division of Allergy and Clinical Immunology, Department of Pediatrics, McGill University, Montreal Children's Hospital, Montreal, QC, Canada.

This case report describes a 14-year-old boy who presented to the emergency department with symptoms of severe anemia. He was diagnosed with autoimmune hemolytic anemia, and on further investigation, it was noted that he had no functioning T cells. Despite no antecedent history of severe infection, he was worked up for a severe combined immunodeficiency, and was found to have a compound hypomorphic mutation in an enzyme responsible for recombination of the B- and T-cell receptors. He was subsequently diagnosed with severe combined immunodeficiency, presenting with autoimmunity, and received a bone marrow transplant. As our knowledge of the immune system continues to expand, we are learning that dysregulation can occur in any one of the complex immune pathways, and may have a variety of clinical presentations. A high index of suspicion for immune defects should be maintained in cases of atypical or severe infections, autoimmunity or malignancy, particularly by the general practitioner, who is often the first to encounter these challenging patients.
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http://dx.doi.org/10.1111/ejh.12148DOI Listing
September 2013

Critical upper airway obstruction in sporadic angioedema responding to C1-esterase inhibitor.

BMJ Case Rep 2013 May 8;2013. Epub 2013 May 8.

Division of Paediatric Allergy and Clinical Immunology, Department of Paediatrics, Montreal Children's Hospital, McGill University Health Center, Montreal, Canada.

We describe a case of recurrent oropharyngeal angioedema in a 16-year-old boy with a history of sickle cell disease and thrombocytopenia and with no family history of angioedema. Emergency treatment of angioedema with C1-esterase inhibitor (C1-INH) provided immediate relief, avoiding the placement of a surgical airway. Further evaluation has shown C1-INH to be normal in quantity and function, with normal complement studies during acute attacks. Genetic testing revealed no abnormality in the factor XII gene. Our case exemplifies that even in cases of sporadic angioedema, treatment with C1-INH may be an effective and life-saving management strategy.
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http://dx.doi.org/10.1136/bcr-2013-009616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669871PMC
May 2013

Autosomal dominant cases of chronic mucocutaneous candidiasis segregates with mutations of signal transducer and activator of transcription 1, but not of Toll-like receptor 3.

J Pediatr 2013 Jul 26;163(1):277-9. Epub 2013 Mar 26.

Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, McGill University Health Center, Montreal, Quebec, Canada.

We report a family with autosomal dominant chronic mucocutaneous candidiasis as well as recurrent viral infections that segregate with a novel signal transducer and activator of transcription 1 (STAT1) mutation. Prophylactic treatment with fluconazole and immunoglobulin replacement has been initiated, with good clinical response.
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http://dx.doi.org/10.1016/j.jpeds.2013.02.040DOI Listing
July 2013

Intravenous immunoglobulin attenuates airway inflammation through induction of forkhead box protein 3-positive regulatory T cells.

J Allergy Clin Immunol 2012 Jun 5;129(6):1656-65.e3. Epub 2012 May 5.

Meakins Christie Laboratories, McGill University Health Center-Research Institute, Montreal, Quebec, Canada.

Background: Intravenous immunoglobulin (IVIG) is a frequently used disease-modifying therapy for a large spectrum of autoimmune and inflammatory conditions, yet its mechanisms of action are incompletely understood. Using a robust murine model of antigen-driven allergic airways disease, we have demonstrated that IVIG markedly improves ovalbumin (OVA)-induced airway hyperresponsiveness characterized by 4- to 6-fold enhancement in regulatory T (Treg) cells in pulmonary and associated lymphoid tissues.

Objective: We sought to determine whether IVIG induces antigen-specific Treg cells and to address cellular interactions that lead to induction of Treg cells by IVIG.

Methods: C57Bl/6 mice were sensitized and challenged by means of intranasal OVA exposure. IVIG or albumin control was administered 24 hours before challenge. Treg cells were tracked by using green fluorescent protein (GFP)-forkhead box protein 3 (Foxp3) knock-in reporter mice (Foxp3(GFP)), and Treg cell and dendritic cell (DC) phenotypes and activities were elucidated by using coculture and flow cytometry.

Results: IVIG therapy of OVA-sensitized and OVA-challenged mice induced antigen-specific forkhead box protein 3 (Foxp3)-positive Treg cells from non-Treg cell precursors. The induced Treg cells home specifically to the lungs and draining lymph nodes and have greatly potentiated suppressive activity compared with that seen in Treg cells purified from control mice. Induction of Treg cells is mediated by tolerogenic DCs generated after IVIG exposure. Compared with albumin-treated, OVA-exposed mice, IVIG-primed DCs express altered Notch ligands, including increased Delta-4 and reduced Jagged-1 levels, reflecting decreased T(H)2 polarization. Furthermore, IVIG-primed DCs can stimulate Treg cell differentiation from uncommitted Foxp3(-)CD4(+) T cells ex vivo, and adoptive transfer of IVIG-primed DCs abrogates airway hyperresponsiveness and induces Treg cells.

Conclusion: The anti-inflammatory effects of IVIG therapy can be mediated by the immunomodulation of DCs, creating a bridge that induces antigen-specific, highly suppressive Treg cells.
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http://dx.doi.org/10.1016/j.jaci.2012.02.050DOI Listing
June 2012

Mannose binding lectin deficiency: more than meets the eye.

Clin Med Insights Pediatr 2012 5;6:89-94. Epub 2012 Nov 5.

McGill University, Montreal Children's Hospital, Montreal, Canada.

This case report describes a 5-year-old boy who presented to the emergency department with clinical symptoms and chest X-ray findings suggestive of pneumonia. Further history revealed multiple other infections, and workup for immunodeficiency revealed a deficiency of mannose-binding lectin (MBL), a pattern recognition receptor involved in activation of the complement system. Innate immunodeficiency may be more common than currently appreciated, with mutations of MBL affecting up to 50% of individuals in some populations. While pneumonia is a common presentation in the Pediatric Emergency Department, clinical presentations of children with defects of innate immunity can be unpredictable. Children may initially appear well with sudden deterioration. These cases pose particular challenges to physicians, and the level of suspicion for innate defects must remain high. It is crucial to identify patients with such impairments to better manage and prevent future complications.
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http://dx.doi.org/10.4137/CMPed.S9860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620812PMC
May 2013

Primary immunodeficiency.

Allergy Asthma Clin Immunol 2011 Nov 10;7 Suppl 1:S11. Epub 2011 Nov 10.

McGill University, Montreal, Quebec, Canada.

Primary immunodeficiency disorder (PID) refers to a heterogeneous group of over 130 disorders that result from defects in immune system development and/or function. PIDs are broadly classified as disorders of adaptive immunity (i.e., T-cell, B-cell or combined immunodeficiencies) or of innate immunity (e.g., phagocyte and complement disorders). Although the clinical manifestations of PIDs are highly variable, most disorders involve at least an increased susceptibility to infection. Early diagnosis and treatment are imperative for preventing significant disease-associated morbidity and, therefore, consultation with a clinical immunologist is essential. PIDs should be suspected in patients with: recurrent sinus or ear infections or pneumonias within a 1 year period; failure to thrive; poor response to prolonged use of antibiotics; persistent thrush or skin abscesses; or a family history of PID. Patients with multiple autoimmune diseases should also be evaluated. Diagnostic testing often involves lymphocyte proliferation assays, flow cytometry, measurement of serum immunoglobulin (Ig) levels, assessment of serum specific antibody titers in response to vaccine antigens, neutrophil function assays, stimulation assays for cytokine responses, and complement studies. The treatment of PIDs is complex and generally requires both supportive and definitive strategies. Ig replacement therapy is the mainstay of therapy for B-cell disorders, and is also an important supportive treatment for many patients with combined immunodeficiency disorders. The heterogeneous group of disorders involving the T-cell arm of the adaptive system, such as severe combined immunodeficiency (SCID), require immune reconstitution as soon as possible. The treatment of innate immunodeficiency disorders varies depending on the type of defect, but may involve antifungal and antibiotic prophylaxis, cytokine replacement, vaccinations and bone marrow transplantation. This article provides a detailed overview of the major categories of PIDs and strategies for the appropriate diagnosis and management of these rare disorders.
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http://dx.doi.org/10.1186/1710-1492-7-S1-S11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245434PMC
November 2011

Efficacy and safety of subcutaneous vivaglobin® replacement therapy in previously untreated patients with primary immunodeficiency: a prospective, multicenter study.

J Clin Immunol 2011 Dec 20;31(6):952-61. Epub 2011 Sep 20.

Hospital St. Georg, GmbH Leipzig, Academic Teaching Hospital of the University of Leipzig, Delitzscher Straße 141, 04129, Leipzig, Germany.

Treatment of primary immunodeficiency (PI) is typically initiated with intravenous immunoglobulin (IVIG) loading and then continued with IVIG or subcutaneous IgG (SCIG). This prospective, open-label, multicenter, 6-month study evaluated a new regimen of initiating IgG therapy with SCIG in 18 previously untreated patients. In the loading phase, SCIG 100 mg/kg was administered for five consecutive days (total loading dose 500 mg/kg). During the maintenance phase, patients self-infused SCIG 100 mg/kg/week at home. The primary efficacy endpoint of IgG levels ≥5 g/L on day 12 was achieved in 17 patients (94.4%; 95% CI 0.727, 0.999). The rate of infections was 3.95 episodes/patient/year. Improvement was found in many subscales of the health-related quality of life questionnaires. SCIG treatment was well tolerated, with no related serious adverse events (AEs). Nine (50%) patients experienced related AEs, including local reactions (rate 0.105 events/infusion). The results suggest that therapy of newly diagnosed patients with PI can be initiated directly with SCIG.
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http://dx.doi.org/10.1007/s10875-011-9588-5DOI Listing
December 2011

Cognitive Impairment among Older Adults in the Emergency Department.

West J Emerg Med 2011 Feb;12(1):56-62

University of Pennsylvania, Philadelphia, PA.

Background: Within the next 30 years, the number of visits older adults will make to emergency departments (EDs) is expected to double from 16 million, or 14% of all visits, to 34 million and comprise nearly a quarter of all visits.

Objective: The objectives of this study were to determine prevalence rates of cognitive impairment among older adults in the ED and to identify associations, if any, between environmental factors unique to the ED and rates of cognitive impairment.

Methods: A cross-sectional observational study of adults 65 and older admitted to the ED of a large, urban, tertiary academic health center was conducted between September 2007 and May 2008. Patients were screened for cognitive impairment in orientation, recall and executive function using the Six-Item Screen (SIS) and the CLOX1, clock drawing task. Cognitive impairment among this ED population was assessed and both patient demographics and ED characteristics (crowding, triage time, location of assessment, triage class) were compared through adjusted generalized linear models.

Results: Forty-two percent (350/829) of elderly patients presented with deficits in orientation and recall as assessed by the SIS. An additional 36% of elderly patients with no impairment in orientation or recall had deficits in executive function as assessed by the CLOX1. In full model adjusted analyses patients were more likely to screen deficits in orientation and recall (SIS) if they were 85 years or older (Relative Risk [RR]=1.63, 95% Confidence Interval [95% CI]=1.3-2.07), black (RR=1.85, 95% CI=1.5-2.4) and male (RR=1.42, 95% CI=1.2-1.7). Only age was significantly associated with executive functioning deficits in the ED screened using the clock drawing task (CLOX1) (75-84 years: RR=1.35, 95% CI= 1.2-1.6; 85+ years: RR=1.69, 95% CI= 1.5-2.0).

Conclusion: These findings have several implications for patients seen in the ED. The SIS coupled with a clock drawing task (CLOX1) provide a rapid and simple method for assessing and documenting cognition when lengthier assessment tools are not feasible and add to the literature on the use of these tools in the ED. Further research on provider use of these tools and potential implication for quality improvement is needed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088375PMC
February 2011