Publications by authors named "Teresa Caballero"

71 Publications

Decreasing Attacks and Improving Quality of Life through a Systematic Management Program for Patients with Hereditary Angioedema.

Int Arch Allergy Immunol 2021 Mar 3:1-12. Epub 2021 Mar 3.

Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil,

Introduction: Prevention of attacks is a major goal in management of patients with hereditary angioedema (HAE). We aimed to investigate the effects of a systematic intervention for HAE patients.

Methods: Thirty-three patients with HAE with C1-inhibitor deficiency, belonging to a single family, participated in a management program coordinated by an allergist/immunologist. Angioedema attacks before intervention were ascertained by interviews and emergency room charts and recorded prospectively by patients or caregivers after enrollment. Mean number of attacks/month was compared at 12 months preintervention and 8 and 14 months within intervention. Patient-reported outcome instruments were used to assess quality of life, including HAE Quality of Life (HAE-QoL) questionnaire, psychological conditions, and work impairment, at baseline and 8 and 14 months within intervention. Data were stored in REDCap platform and analyzed by adjusted Bayesian models of double Poisson regression.

Results: Mean number of attacks/month significantly decreased (95% credible interval [CrI] excluding 0) from 1.15 preintervention to 0.25 and 0.23, 8 and 14 months within intervention, with mean decreases of -0.89 (95% CrI: -1.21 to -0.58) and -0.92 (95% CrI: -1.22 to -0.60), respectively. HAE-QoL scores showed mean total increases of 15.2 (95% CrI: 1.23-29.77) and 26 (95% CrI: 14.56-39.02) at 8 and 14 months within the study, as compared to baseline, revealing marked improvement in quality of life. Significant increase in role-emotional and reduction of depression, stress, and anxiety were observed at 14 months.

Conclusion: A systematic approach integrating HAE-specific care with effective handling of psychological issues decreased the number of attacks and improved quality of life, targets for best practice in HAE.
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http://dx.doi.org/10.1159/000513896DOI Listing
March 2021

Long-term health-related quality of life in patients treated with subcutaneous C1-inhibitor replacement therapy for the prevention of hereditary angioedema attacks: findings from the COMPACT open-label extension study.

Orphanet J Rare Dis 2021 Feb 15;16(1):86. Epub 2021 Feb 15.

University College Hospital, London, UK.

Background: Long-term prophylaxis with subcutaneous C1-inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) in patients with hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE) was evaluated in an open-label extension follow-up study to the international, double-blind, placebo-controlled COMPACT study. The current analysis evaluated patient-reported health-related quality of life (HRQoL) data from 126 patients in the open-label extension study randomized to treatment with C1-INH(SC) 40 IU/kg (n = 63) or 60 IU/kg (n = 63) twice weekly for 52 weeks. HRQoL was evaluated at the beginning of the open-label study and at various time points using the European Quality of Life-5 Dimensions Questionnaire (EQ-5D), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication. The disease-specific Angioedema Quality of Life Questionnaire (AE-QoL) and HAE quality of life questionnaire (HAE-QoL) instruments were administered in a subset of patients. Statistical significance was determined by change-from-baseline 95% confidence intervals (CIs) excluding zero. No adjustment for multiplicity was done.

Results: Mean baseline EQ-5D scores (Health State Value, 0.90; Visual Analog Scale, 81.32) were slightly higher (better) than United States population norms (0.825, 80.0, respectively) and mean HADS anxiety (5.48) and depression (2.88) scores were within "normal" range (0-7). Yet, patients using C1-INH(SC) 60 IU/kg demonstrated significant improvement from baseline to end-of-study on the EQ-5D Health State Value (mean change [95% CI], 0.07 [0.01, 0.12] and Visual Analog Scale (7.45 [3.29, 11.62]). In the C1-INH(SC) 60 IU/kg group, there were significant improvements in the HADS anxiety scale (mean change [95% CI], - 1.23 [- 2.08, - 0.38]), HADS depression scale (- 0.95 [- 1.57, - 0.34]), and WPAI-assessed presenteeism (mean change [95% CI], - 23.33% [- 34.86, - 11.81]), work productivity loss (- 26.68% [- 39.92, - 13.44]), and activity impairment (- 16.14% [- 26.36, - 5.91]). Clinically important improvements were achieved in ≥ 25% of patients for all domains except WPAI-assessed absenteeism (which was very low at baseline). Mean AE-QoL total score by visit ranged from 13.39 to 17.89 (scale 0-100; lower scores = less impairment). Mean HAE-QoL global scores at each visit (115.7-122.3) were close to the maximum (best) possible score of 135.

Conclusions: Long-term C1-INH(SC) replacement therapy in patients with C1-INH-HAE leads to significant and sustained improvements in multiple measures of HRQoL. Trial registration A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema, NCT02316353. Registered December 12, 2014, https://clinicaltrials.gov/ct2/show/NCT02316353 .
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http://dx.doi.org/10.1186/s13023-020-01658-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885603PMC
February 2021

In Search of an Association Between Genotype and Phenotype in Hereditary Angioedema due to C1-INH Deficiency.

Clin Rev Allergy Immunol 2021 Jan 19. Epub 2021 Jan 19.

Allergy Department, Hospital Universitario La Paz, Madrid, Spain.

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is caused by mutations affecting the SERPING1 gene. Adult patients (≥ 18 years old) diagnosed with C1-INH-HAE were clustered according to a modified SERPING1 gene mutation classification [5]. Demographic, clinical, and laboratory data were studied. Published manuscripts on the genotype/phenotype relationship were reviewed. Eighty-eight patients participated in the study, with 78 having a classifiable mutation. We compared the data in the 3 largest groups: class 0 only (n = 32), class II only (n = 18), class III only (n = 22). Antigenic C4 and C1 inhibitors were higher in class II (p = 0.008 and p = 0.02, respectively), and facial attacks in the last 6 months were more frequent in class III (p = 0.04)). All the other differences were non-significant. Twelve manuscripts on phenotype/genotype correlation were found: missense mutations in SERPING1 gene were associated with delay in disease onset and lower severity score in some studies, whereas the CC F12-C46T/C polymorphism produced earlier disease onset. Our study shows minimal differences regarding clinical phenotype in patients with class 0, II, and III SERPING1 gene mutations, with a tendency to class III having a more severe phenotype. The study should be performed in a larger sample to confirm if they are significant.We propose that larger multicenter, international studies are performed, comparing different SERPING1 gene mutation classifications, combining polymorphisms in other involved genes (kallikrein-kinin system, regulation of vasculature, plasminogen activation) and using different variables and clinical scores to assess C1-INH-HAE disease activity and/or severity in order to study possible genotype/phenotype relationships.
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http://dx.doi.org/10.1007/s12016-021-08834-9DOI Listing
January 2021

Quality of life in patients with hereditary angioedema in Canada.

Ann Allergy Asthma Immunol 2021 Jan 13. 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
January 2021

Mediastinal Angioedema: A Rare Manifestation of Hereditary Angioedema.

J Allergy Clin Immunol Pract 2021 Jan 7;9(1):477-478. Epub 2020 Nov 7.

Allergy Department, Hospital Universitario La Paz, Madrid, Spain; Hospital La Paz Health Research Institute (IdiPaz), Madrid, Spain; Biomedical Research Network on Rare Diseases (CIBERER U754), Madrid, Spain.

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http://dx.doi.org/10.1016/j.jaip.2020.09.058DOI Listing
January 2021

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant.

Front Genet 2020 10;11:1033. Epub 2020 Sep 10.

Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain.

Background: Hereditary angioedema due to the Thr328Lys variant in the coagulation factor XII (HAE-FXII) affects mainly women in whom the symptomatology is dependent on high estrogen levels. Clinical variability and incomplete penetrance are challenging features that hinder the diagnosis and management of HAE-FXII. The c.-4T>C Kozak polymorphism is the only common variation accounting for FXII plasma levels and was previously shown to modify the course of HAE due to C1-Inhibitor deficiency.

Objectives: To assess the influence of the c.-4T>C polymorphism on disease expression in 39 Spanish HAE-FXII index patients.

Methods: The c.-4T>C polymorphism was sequenced by the standard Sanger method, and HAE severity was calculated according to the score by Cumming et al. (2003) The activation of the contact system was quantified by the kallikrein-like activity of plasma in chromogenic assays upon activation with high-molecular-weight dextran sulfate.

Results: The c.-4CC genotype was overrepresented in the studied cohort: 82% were CC-homozygous (expected frequency = 59%) and 18% were CT-heterozygous (expected frequency = 39%) ( = 0.001). Patients with a c.-4CC genotype exhibited higher kallikrein-like activity (0.9659 ± 0.1136) than those with a c.-4TC genotype (0.7645 ± 0.1235) ( = 0.024) or healthy donors. Moreover, the polymorphism influenced HAE-FXII severity score (c.-4CC = 4.43 ± 2.28 vs c.-4TC = 2.0 ± 1.15; = 0.006) but not the degree of estrogen dependence or time until remission.

Conclusion: The c.-4T>C polymorphism is overrepresented in a Spanish HAE-FXII cohort and significantly influences the degree of contact system activation and the clinical severity of the disease.
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http://dx.doi.org/10.3389/fgene.2020.01033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549737PMC
September 2020

Long-Term Efficacy of Subcutaneous C1 Inhibitor in Pediatric Patients with Hereditary Angioedema.

Pediatr Allergy Immunol Pulmonol 2020 Sep 16;33(3):136-141. Epub 2020 Sep 16.

Medical Research of Arizona, Scottadale, Arizona, USA.

Hereditary angioedema (HAE) due to C1 inhibitor (C1INH) deficiency is characterized by recurrent attacks of edema of the skin and mucosal tissues. Symptoms usually present during childhood (mean age at first attack, 10 years). Earlier symptom onset may predict a more severe disease course. Subcutaneous (SC) C1INH is indicated for routine prophylaxis to prevent HAE attacks in adolescents and adults. We analyzed the long-term efficacy of C1INH (SC) in subjects ≤17 years old treated in an open-label extension (OLE) of the pivotal phase III Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1 Inhibitor Replacement Therapy (COMPACT) trial. Eligible subjects (age ≥6 years, with ≥4 attacks over 2 consecutive months before entry into the OLE or placebo-controlled COMPACT trial) were treated with C1INH (SC) 40 or 60 IU/kg twice weekly for 52-140 weeks. Subgroup analyses by age (≤17 vs. >17 years) were performed for key efficacy endpoints. Ten subjects were ≤17 years old [mean (range) age, 13.3 (8-16) years, 3 subjects <12 years old; exposure range, 51-133 weeks]. All 10 pediatric subjects experienced ≥50% reduction (mean, 93%) in number of attacks versus the prestudy period, with a 97% reduction in the median number of attacks/month (0.11). All subjects had <1 attack/4-week period and 4 had <1 attack/year (1 subject was attack free). No subject discontinued treatment due to a treatment-related adverse event. Data from pediatric subjects treated with C1INH (SC) for up to 2.55 years and adult subjects revealed similar efficacy. C1INH (SC) is effective and well tolerated as long-term prophylaxis in children, adolescents, and adults with HAE.
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http://dx.doi.org/10.1089/ped.2020.1143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499895PMC
September 2020

Definition, aims, and implementation of GA LEN/HAEi Angioedema Centers of Reference and Excellence.

Authors:
Marcus Maurer Werner Aberer Rosana Agondi Mona Al-Ahmad Maryam Ali Al-Nesf Ignacio Ansotegui Rand Arnaout Luisa Karla Arruda Riccardo Asero Emel Aygören-Pürsün Aleena Banerji Andrea Bauer Moshe Ben-Shoshan Alejandro Berardi Jonathan A Bernstein Stephen Betschel Carsten Bindslev-Jensen Mojca Bizjak Isabelle Boccon-Gibod Konrad Bork Laurence Bouillet Henrik Balle Boysen Nicholas Brodszki Sigurd Broesby-Olsen Paula Busse Thomas Buttgereit Anette Bygum Teresa Caballero Régis A Campos Mauro Cancian Ivan Cherrez-Ojeda Danny M Cohn Célia Costa Timothy Craig Paulo Ricardo Criado Roberta F Criado Dorottya Csuka Joachim Dissemond Aurélie Du-Thanh Luis Felipe Ensina Ragıp Ertaş José E Fabiani Claudio Fantini Henriette Farkas Silvia Mariel Ferrucci Ignasi Figueras-Nart Natalia L Fili Daria Fomina Atsushi Fukunaga Asli Gelincik Ana Giménez-Arnau Kiran Godse Mark Gompels Margarida Gonçalo Maia Gotua Richard Gower Anete S Grumach Guillermo Guidos-Fogelbach Michihiro Hide Natalia Ilina Naoko Inomata Thilo Jakob Dario O Josviack Hye-Ryun Kang Allen Kaplan Alicja Kasperska-Zając Constance Katelaris Aharon Kessel Andreas Kleinheinz Emek Kocatürk Mitja Košnik Dorota Krasowska Kanokvalai Kulthanan M Sendhil Kumaran José Ignacio Larco Sousa Hilary J Longhurst William Lumry Andrew MacGinnitie Markus Magerl Michael P Makris Alejandro Malbrán Alexander Marsland Inmaculada Martinez-Saguer Iris V Medina Raisa Meshkova Martin Metz Iman Nasr Jan Nicolay Chikako Nishigori Isao Ohsawa Kemal Özyurt Nikolaos G Papadopoulos Claudio A S Parisi Jonathan Grant Peter Wolfgang Pfützner Todor Popov Nieves Prior German D Ramon Adam Reich Avner Reshef Marc A Riedl Bruce Ritchie Heike Röckmann-Helmbach Michael Rudenko Andaç Salman Mario Sanchez-Borges Peter Schmid-Grendelmeier Faradiba S Serpa Esther Serra-Baldrich Farrukh R Sheikh William Smith Angèle Soria Petra Staubach Urs C Steiner Marcin Stobiecki Gordon Sussman Anna Tagka Simon Francis Thomsen Regina Treudler Solange Valle Martijn van Doorn Lilian Varga Daniel O Vázquez Nicola Wagner Liangchun Wang Christina Weber-Chrysochoou Young-Min Ye Anna Zalewska-Janowska Andrea Zanichelli Zuotao Zhao Yuxiang Zhi Torsten Zuberbier Ricardo D Zwiener Anthony Castaldo

Allergy 2020 08 27;75(8):2115-2123. Epub 2020 Apr 27.

HAE International (HAEi), Fairfax City, VA, USA.

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http://dx.doi.org/10.1111/all.14293DOI Listing
August 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

Elderly versus younger patients with hereditary angioedema type I/II: patient characteristics and safety analysis from the Icatibant Outcome Survey.

Clin Transl Allergy 2019 19;9:37. Epub 2019 Jul 19.

10Department of Dermatology and Allergy, Dermatological Allergology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is characterized by recurrent swelling in subcutaneous or submucosal tissues. Symptoms often begin by age 5-11 years and worsen during puberty, but attacks can occur at any age and recur throughout life. Disease course in elderly patients is rarely reported.

Methods: The Icatibant Outcome Survey (IOS) is an observational study evaluating the safety, tolerability, and efficacy of icatibant. We conducted descriptive analyses in younger (age < 65 years) versus elderly patients (age ≥ 65 years). Here, we report patient characteristics and safety-related findings.

Results: As of February 2018, 872 patients with C1-INH-HAE type I/II were enrolled, of whom 100 (11.5%) were ≥ 65 years old. Significant differences between elderly versus younger patients, respectively, were noted for median age at symptom onset (17.0 vs 12.0 years), age at diagnosis (41.0 vs 19.4 years), and delay between symptom onset and diagnosis (23.9 vs 4.8 years) (P ≤ 0.0001 for all). Median age at diagnosis was significantly higher in elderly patients regardless of family history (P < 0.0001). Throughout the study, icatibant was used to treat 6798 attacks in 574 patients, with 63 elderly patients reporting 715 (10.5%) of the icatibant-treated attacks. No serious adverse events (SAEs) in elderly patients were judged to be possibly related to icatibant, whereas two younger patients reported three possibly related SAEs. Excluding off-label use and pregnancy (evaluated for regulatory purposes), the percentage of patients with at least one possibly/probably related AE was similar for elderly (2.0%) versus younger patients (2.7%). No deaths linked to icatibant treatment were identified. All related events in elderly patients were attributed to general disorders/administration site conditions, whereas related events in younger patients occurred across various system organ class designations.

Conclusions: Elderly patients with C1-INH-HAE were significantly older at diagnosis and had greater delay in diagnosis than younger patients. Elderly patients contributed to approximately 10% of the icatibant-treated attacks. Our analysis found similar AE rates (overall and possibly/probably related) in icatibant-treated elderly versus younger patients, despite the fact that elderly patients had significantly more comorbidities and were receiving a greater number of concomitant medications. Our analysis did not identify any new or unexpected safety concerns.
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http://dx.doi.org/10.1186/s13601-019-0272-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639901PMC
July 2019

Long-Term Outcomes with Subcutaneous C1-Inhibitor Replacement Therapy for Prevention of Hereditary Angioedema Attacks.

J Allergy Clin Immunol Pract 2019 Jul - Aug;7(6):1793-1802.e2. Epub 2019 Feb 15.

CSL Behring LLC, King of Prussia, Pa.

Background: For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT).

Objective: To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC).

Methods: Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353).

Results: A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment.

Conclusions: In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms.
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http://dx.doi.org/10.1016/j.jaip.2019.01.054DOI Listing
September 2020

Improvement in diagnostic delays over time in patients with hereditary angioedema: findings from the Icatibant Outcome Survey.

Clin Transl Allergy 2018 12;8:42. Epub 2018 Oct 12.

2Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité-Universitätsmedizin Berlin, Berlin, Germany.

The objective of this analysis was to evaluate the change over time in age at first symptoms, age at diagnosis, and delay in diagnosis using data from the Icatibant Outcome Survey (IOS). Patients with a diagnosis of C1-INH-HAE who were born before the year 1990 and who were diagnosed before they reached 25 years of age were included in the analysis. Both age at diagnosis and delay in diagnosis of C1-INH-HAE appear to decline with later decade of birth, despite wide variation across the countries assessed, suggesting that improved disease awareness causes increased rates of earlier diagnosis over time. Our findings demonstrate that some patients are still experiencing long delays to diagnosis, indicating an ongoing need for improved disease awareness.
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http://dx.doi.org/10.1186/s13601-018-0229-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182796PMC
October 2018

Pediatricians diagnosed few patients with childhood-presented hereditary angioedema: Icatibant Outcome Survey findings.

J Allergy Clin Immunol Pract 2019 03 28;7(3):1078-1080. Epub 2018 Aug 28.

Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2018.07.047DOI Listing
March 2019

Microbiome and Allergic Diseases.

Front Immunol 2018 17;9:1584. Epub 2018 Jul 17.

Research Laboratory and Allergy Unit, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario, Universidad de Málaga, ARADyAL, Malaga, Spain.

Allergic diseases, such as respiratory, cutaneous, and food allergy, have dramatically increased in prevalence over the last few decades. Recent research points to a central role of the microbiome, which is highly influenced by multiple environmental and dietary factors. It is well established that the microbiome can modulate the immune response, from cellular development to organ and tissue formation exerting its effects through multiple interactions with both the innate and acquired branches of the immune system. It has been described at some extent changes in environment and nutrition produce dysbiosis in the gut but also in the skin, and lung microbiome, inducing qualitative and quantitative changes in composition and metabolic activity. Here, we review the potential role of the skin, respiratory, and gastrointestinal tract (GIT) microbiomes in allergic diseases. In the GIT, the microbiome has been proven to be important in developing either effector or tolerant responses to different antigens by balancing the activities of Th1 and Th2 cells. In the lung, the microbiome may play a role in driving asthma endotype polarization, by adjusting the balance between Th2 and Th17 patterns. Bacterial dysbiosis is associated with chronic inflammatory disorders of the skin, such as atopic dermatitis and psoriasis. Thus, the microbiome can be considered a therapeutical target for treating inflammatory diseases, such as allergy. Despite some limitations, interventions with probiotics, prebiotics, and/or synbiotics seem promising for the development of a preventive therapy by restoring altered microbiome functionality, or as an adjuvant in specific immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2018.01584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056614PMC
July 2018

Safety, effectiveness, and impact on quality of life of self-administration with plasma-derived nanofiltered C1 inhibitor (Berinert®) in patients with hereditary angioedema: the SABHA study.

Orphanet J Rare Dis 2018 04 10;13(1):51. Epub 2018 Apr 10.

Allergy Department, Hospital La Paz Institute for Health Research, Madrid, Spain.

Background: Hereditary angioedema with C1 inhibitor deficiency is a disabling, potentially fatal condition characterized by recurrent episodes of swelling. Self-treatment is recommended, in order to reduce admissions to the Emergency Room and the time between the onset of the attack and the treatment, resulting in a better treatment outcome and an improved quality of life (QoL). The purpose of this study is to assess the safety, tolerability, and effect on QoL of self-administration of pnf C1-INH for IV use (Berinert®).

Methods: An observational, monocenter, prospective study was designed. Patients referring to a center for angioedema that attended two sessions of self-infusion training course in the period March 2014-July 2015 were enrolled in the study. The primary endpoint was to monitor the safety and feasibility of pnf C1-INH self-infusion. The secondary endpoint was to evaluate the effect of self-infusion on the QoL, by means of the HAE-QoL questionnaire and the need for access to Emergency Room for infusion of Berinert®. Patients' medical history data were collected upon the first visit and questionnaires were filled after each attack treated with Berinert® (diary and Treatment Satisfaction Questionnaire for Medication) and upon the first visit and the follow-ups (HAE-QoL).

Results: Twenty patients were enrolled (median age = 42, IQR: 39-49; 60% females). Fifteen patients completed the study. A total of 189 attacks were recorded (annual median rate of 4 attacks/patient). Patients waited a median of 2 h (IQR: 1-4) before self-administration, and the resolution of the attack occurred after a median of 6 h (IQR: 4-11). Most attacks were abdominal (39%) and peripheral (22%). 92% of the attacks were treated through self-/caregiver-administration. In most attacks no side effects were reported. The number of attacks with side effects decreased over time, from 37% to 13%. Global satisfaction grew over time during the study period, reaching statistical significance over the first 6 months. The median total HAE-QoL score at baseline was 86 (IQR: 76-103) and improved in a non-significant manner throughout the study period. 8% of the attacks treated with Berinert® required ER admission/healthcare professional help in the study period, compared with 100% in the 3 years before enrollment (p < 0.0001).

Conclusions: Self-administration of pnf C1-INH is safe, and increases patients' confidence in the treatment, showing also a trend towards an improvement in QoL. It reduces the need for ER admission/healthcare professionals help for the acute attacks, as well as the related costs.
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http://dx.doi.org/10.1186/s13023-018-0797-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891972PMC
April 2018

Effectiveness of icatibant for treatment of hereditary angioedema attacks is not affected by body weight: findings from the Icatibant Outcome Survey, a cohort observational study.

Clin Transl Allergy 2018 23;8:11. Epub 2018 Mar 23.

7Shire, Zug, Switzerland.

Background: Icatibant is a bradykinin B2-receptor antagonist used for the treatment of hereditary angioedema attacks resulting from C1-inhibitor deficiency. Treatment is not adjusted by body weight however the impact of body mass index (BMI) on the effectiveness of icatibant is not documented in the literature. We examined disease characteristics and icatibant treatment effectiveness in patients stratified by BMI in the Icatibant Outcome Survey, an ongoing, international, observational study monitoring the real-world safety and effectiveness of icatibant.

Methods: Attack and treatment characteristics as well as outcomes following treatment with icatibant were compared among patients with underweight, normal, overweight, and obese BMI.

Results: Data from 2697 icatibant-treated attacks in 342 patients (3.5, 44.7, 34.8, and 17.0% patients of underweight, normal, overweight, and obese BMI, respectively) were analyzed. There was no significant difference in the frequency and severity of attacks across BMI groups, although obese patients tended to have more attacks of high severity. There was no impact of BMI on the frequency of laryngeal attacks, but patients with normal BMI had fewer cutaneous attacks and more abdominal attacks. Most attacks (71.9-83.8%) were treated with a single icatibant injection without the need for rescue with plasma-derived C1-inhibitor (pdC1-INH), regardless of BMI. Patients with obese BMI used pdC1-INH as rescue treatment more often (P < 0.0001; P = 0.0232 excluding 2 outliers) and treated attacks earlier than patients with normal BMI (P = 0.007). Furthermore, time to resolution and duration of attack were shorter for patients with high BMI (P < 0.001 for overweight and P < 0.05 for obese versus normal).

Conclusion: Overall, icatibant was comparatively effective in treating attacks in patients across all BMI groups. NCT01034969.
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http://dx.doi.org/10.1186/s13601-018-0195-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870812PMC
March 2018

Health-Related Quality of Life with Subcutaneous C1-Inhibitor for Prevention of Attacks of Hereditary Angioedema.

J Allergy Clin Immunol Pract 2018 Sep - Oct;6(5):1733-1741.e3. Epub 2018 Jan 31.

CSL Behring, King of Prussia, Pa.

Background: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) impairs health-related quality of life (HRQoL).

Objective: The objective of this study was to assess HRQoL outcomes in patients self-administering subcutaneous C1-INH (C1-INH[SC]; HAEGARDA) for routine prevention of HAE attacks.

Methods: Post hoc analysis of data from the placebo-controlled, crossover phase III COMPACT study (Clinical Studies for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy). Ninety patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH(SC) 40 or 60 IU/kg twice weekly for 16 weeks, preceded or followed by 16 weeks of twice weekly placebo injections. All HAE attacks were treated with open-label on-demand treatment as necessary. HRQoL assessments at week 14 (last visit) included the European Quality of Life-5 Dimensions Questionnaire (EQ-5D-3L), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication (TSQM).

Results: Compared with placebo (on-demand treatment alone), treatment with twice weekly C1-INH(SC) (both doses combined) was associated with better EQ-5D visual analog scale general health, less HADS anxiety, less WPAI presenteeism, work productivity loss, and activity impairment, and greater TSQM effectiveness and overall treatment satisfaction. More patients self-reported a "good/excellent" response during routine prevention with C1-INH(SC) compared with on-demand only (placebo prophylaxis) management. For each HRQoL measure, a greater proportion of patients had a clinically meaningful improvement during C1-INH(SC) treatment compared with placebo.

Conclusions: In patients with frequent HAE attacks, a treatment strategy of routine prevention with self-administered twice weekly C1-INH(SC) had a greater impact on improving multiple HAE-related HRQoL impairments, most notably anxiety and work productivity, compared with on-demand treatment alone (placebo prophylaxis).
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http://dx.doi.org/10.1016/j.jaip.2017.12.039DOI Listing
November 2019

Disease Severity, Activity, Impact, and Control and How to Assess Them in Patients with Hereditary Angioedema.

Front Med (Lausanne) 2017 4;4:212. Epub 2017 Dec 4.

Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Hereditary angioedema (HAE) is a group of rare, potentially life-threatening, and frequently debilitating diseases characterized by recurrent, and often with an unpredictable onset, of swelling attacks. HAE is heterogeneous, with considerable differences between its subtypes, patients, and even within the same patient over time. During the past few years, several new on demand and prophylactic therapies have become available for HAE, allowing for individualized treatment. Therefore, to optimize HAE management, it is important to determine in all patients, the severity of their attacks, their disease activity, its therapeutic control, and its impact on their quality of life. In this manuscript, we review the existing tools to assess these aspects of HAE management, many of which are patient-reported outcome instruments. Also, we outline the current gaps of knowledge and what tools are still missing to allow for a comprehensive assessment of all patients with HAE including children.
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http://dx.doi.org/10.3389/fmed.2017.00212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722805PMC
December 2017

Breakthrough attacks in patients with hereditary angioedema receiving long-term prophylaxis are responsive to icatibant: findings from the Icatibant Outcome Survey.

Allergy Asthma Clin Immunol 2017 5;13:31. Epub 2017 Jul 5.

Shire, Zählerweg 10, 6300 Zug, Switzerland.

Background: Patients with hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE) experience recurrent attacks of cutaneous or submucosal edema that may be frequent and severe; prophylactic treatments can be prescribed to prevent attacks. However, despite the use of long-term prophylaxis (LTP), breakthrough attacks are known to occur. We used data from the Icatibant Outcome Survey (IOS) to evaluate the characteristics of breakthrough attacks and the effectiveness of icatibant as a treatment option.

Methods: Data on LTP use, attacks, and treatments were recorded. Attack characteristics, treatment characteristics, and outcomes (time to treatment, time to resolution, and duration of attack) were compared for attacks that occurred with versus without LTP.

Results: Data on 3228 icatibant-treated attacks from 448 patients with C1-INH-HAE were analyzed; 30.1% of attacks occurred while patients were using LTP. Attack rate, attack severity, and the distribution of attack sites were similar across all types of LTP used, and were comparable to the results found in patients who did not receive LTP. Attacks were successfully treated with icatibant; 82.5% of all breakthrough attacks were treated with a single icatibant injection without C1-INH rescue medication. Treatment outcomes were comparable for breakthrough attacks across all LTP types, and for attacks without LTP.

Conclusions: Patients who use LTP should be aware that breakthrough attacks can occur, and such attacks can be severe. Thus, patients with C1-INH-HAE using LTP should have emergency treatment readily available. Data from IOS show that icatibant is effective for the treatment of breakthrough attacks. NCT01034969.
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http://dx.doi.org/10.1186/s13223-017-0203-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497380PMC
July 2017

Burden of Illness and Quality-of-Life Measures in Angioedema Conditions.

Immunol Allergy Clin North Am 2017 08;37(3):597-616

Allergy Department, Hospital Universitario Severo Ochoa, Avenida de Orellana s/n, Leganés, Madrid 28911, Spain.

Burden of illness studies and evaluation of health-related quality of life using validated questionnaires have become an important task in the comprehensive management of angioedema conditions, mainly angioedema associated with chronic spontaneous urticaria and hereditary angioedema caused by C1-inhibitor deficiency. A review of the principal tools and studies is presented. Both diseases present a higher proportion of psychiatric disorders, impair work and studies productivity, and produce high direct and indirect costs. These assessments also have been useful to evaluate the positive impact of new drugs and interventions. More studies are desirable, especially in other types of angioedema disorders, such as hereditary angioedema with normal C1 inhibitor.
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http://dx.doi.org/10.1016/j.iac.2017.04.005DOI Listing
August 2017

Treatment Effect and Safety of Icatibant in Pediatric Patients with Hereditary Angioedema.

J Allergy Clin Immunol Pract 2017 Nov - Dec;5(6):1671-1678.e2. Epub 2017 Jun 7.

Institute for Asthma and Allergy, Chevy Chase, Md.

Background: Clinical manifestations of hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) usually begin in childhood, often intensifying during puberty. Currently there are insufficient efficacy/safety data for HAE therapies in children and adolescents due to the small number of pediatric patients enrolled in studies.

Objective: The objective of this phase 3 study was to evaluate the efficacy/safety of a single subcutaneous dose of icatibant (0.4 mg/kg; maximum 30 mg) in pediatric patients with C1-INH-HAE.

Methods: Patients aged 2 years to younger than 18 years were categorized as prepubertal (children) and pubertal/postpubertal (adolescents). The primary end point was time to onset of symptom relief-earliest time posttreatment to 20% or more improvement in composite symptom score.

Results: Thirty-two patients received icatibant (safety population: 11 children with attack, 10 adolescents without attack, and 11 adolescents with attack). The efficacy population consisted of 11 children and 11 adolescents with edematous attacks. Most attacks in the efficacy population (16 [72.7%]) were cutaneous, 5 (22.7%) were abdominal, and 1 (4.5%) was both cutaneous and abdominal; none was laryngeal. Overall, the median time to onset of symptom relief was 1.0 hour, the same for children and adolescents. Thirty-two treatment-emergent adverse events (all mild or moderate) occurred in 9 (28.1%) patients. Gastrointestinal symptoms were most common (9 events in 3 [9.4%] patients). Injection-site reactions affected most (90.6%) patients (particularly erythema and swelling), but almost all resolved by 6 hours postdose. Icatibant demonstrated a monophasic plasma concentration-time profile. Time to peak concentration was approximately 0.5 hours postdose.

Conclusions: Symptom relief was rapid, and a single icatibant injection in pediatric patients with C1-INH-HAE was well tolerated (ClinicalTrials.gov identifier, NCT01386658).
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http://dx.doi.org/10.1016/j.jaip.2017.04.010DOI Listing
June 2018

Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.

N Engl J Med 2017 03;376(12):1131-1140

From Barts Health NHS Trust (H.L.) and St. John's Institute of Dermatology, Guy's Hospital (C.G.), London, and the Clinical Investigation and Research Unit, Royal Sussex County Hospital, Brighton (M.T.) - all in the United Kingdom; Ospedale Luigi Sacco-U.O. Medicina Generale, Milan (M.C.), and the Department of Internal Medicine, University of Catania, Catania (S.N.) - both in Italy; Department of Medicine and Pediatrics, Penn State Hershey Allergy, Asthma, and Immunology, Hershey (T. Craig), and CSL Behring, King of Prussia (D.B.-K., J.E., D.P.) - both in Pennsylvania; the Department of Dermatology, Johannes Gutenberg University Mainz, Mainz (K.B.), and CSL Behring, Marburg (H. Feuersenger, J.-P.L., T.M., I.P.) - both in Germany; Baker Allergy, Asthma and Dermatology Research Center, Portland, OR (J. Baker); Institute for Asthma and Allergy, Chevy Chase, MD (H.H.L.); Allergy and Immunology Unit, Chaim Sheba Medical Center, Tel Hashomer (A.R.), and Allergy and Immunology Unit, Tel Aviv Sourasky Medical Center, Tel Aviv (S.K.) - both in Israel; Clinical Research Center of Alabama, Birmingham (J. Bonner, J.A.); Department of Internal Medicine, Allergy Section Cincinnati, University of Cincinnati College of Medicine, Cincinnati (J.A.B.), and Toledo Institute of Clinical Research, Toledo (S.M.R.) - both in Ohio; Allergy Asthma Research Associates Research Center, Dallas (W.R.L.); Hungarian Angioedema Center, Third Department of Internal Medicine, Semmelweis University, Budapest (H. Farkas); the Department of Medicine, Immunology, and Allergy, Campbelltown Hospital, Campbelltown, NSW, Australia (C.H.K.); the Department of Clinical Immunology and Allergy, St. Michael's Hospital, Toronto (G.L.S.), Centre de Recherche Appliqué en Allergie de Québec, Quebec, QC (J.H.), McMaster University, Hamilton, ON (P.K.K.), Ottawa Allergy Research and University of Ottawa Medical School, Ottawa (W.Y.), and University of Alberta Hospital, Edmonton (B.R.) - all in Canada; Allergy and Asthma Clinical Research, Walnut Creek (J.J.), University of California, San Diego School of Medicine, La Jolla (M.R., B.L.Z.), and 705 W. La Veta Ave., Suite 101, Orange (D.S.L.) - all in California; Medical Research of Arizona, Scottsdale (M.E.M.); Hospital General Universitario Gregorio Marañón and Biomedical Research Network on Rare Diseases-U761, Institute for Health Research, Gregorio Marañón (M.L.B.), and the Allergy Department, Hospital La Paz Institute for Health Research, Biomedical Research Network on Rare Diseases (T. Caballero), Madrid, the Allergy Department, IIS Hospital Universitario La Fe, Valencia (M.D.H.), and Hospital Universitario Vall d'Hebron, Barcelona (M.G.) - all in Spain; Asthma and Allergy Association, Colorado Springs, CO (R.N.); Department of Internal Medicine, Virginia Commonwealth University, Richmond (L.B.S.); Spitalul Clinic Municipal, Cluj-Napoca, Romania (I.C.); Vital Prospects Clinical Research Institute, Tulsa, OK (I.H.); Institute of Clinical Immunology and Allergology, University Hospital, Hradec Kralove, Czech Republic (P.K.); Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston (A.B.); and Marycliff Allergy Specialists, Spokane, WA (R.G.G.).

Background: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks.

Methods: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used.

Results: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo.

Conclusions: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).
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http://dx.doi.org/10.1056/NEJMoa1613627DOI Listing
March 2017

Sensitization to microarrayed species-specific plant components precedes that of cross-reacting allergens.

Pediatr Allergy Immunol 2017 May 22;28(3):288-291. Epub 2017 Mar 22.

Department of Allergy, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.

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http://dx.doi.org/10.1111/pai.12701DOI Listing
May 2017

Hereditary angioedema: health-related quality of life in Canadian patients as measured by the SF-36.

Allergy Asthma Clin Immunol 2017 19;13. Epub 2017 Jan 19.

Division of Clinical Immunology and Allergy, St. Michael's Hospital, Bond Street, 4 CC Specialty Clinics, Toronto, ON M5B 1W8 Canada.

Background: Hereditary angioedema (HAE) is a rare but serious condition characterized by recurrent spontaneous attacks of angioedema affecting superficial tissues of upper respiratory and gastrointestinal tracts. The potentially fatal and disfiguring nature of HAE impacts the health-related quality of life (HRQoL) of patients with this condition.

Objectives: To assess the health-related quality of life of Canadian patients with HAE using the 36-item Short-Form Health Survey (SF-36v2).

Methods: Twenty-one patients living in Canada over age 18 with known diagnosis of hereditary angioedema due to C1-INH deficiency (HAE), completed the SF-36v2 (generic HRQoL questionnaire). Results were compared to Canadian normative data by converting the SF-36 scores into z scores.

Results: The SF-36v2 showed a significant reduction in general health (p = 0.0063) in patients with HAE when compared with healthy Canadians. Percentage of patients with z scores below 0.8 (large effect) was 47.6% for general health subscale, 33.3% for bodily pain and vitality subscales and 28.6% for physical component scores. Mean scores of eight dimensions ranged from 57.7 to 88.9. Mean Physical and mental component scores were 49.1 and 50.4. Internal consistency of evaluation was demonstrated by Cronbach's alpha value above 0.7 for all scales. General perception of health was significantly different in these patients, compared to Canadian normative data.

Conclusions: This study of Canadian patients with HAE shows that General Health is most frequently affected followed by Bodily Pain and Vitality, as measured by SF-36v2. The SF-36v2 offers valuable insight to assess quality of life in patients with HAE, however a larger number of Canadian patients and specific tools for assessment are needed for better evaluation.
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http://dx.doi.org/10.1186/s13223-016-0176-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244704PMC
January 2017

Misdiagnosis trends in patients with hereditary angioedema from the real-world clinical setting.

Ann Allergy Asthma Immunol 2016 10;117(4):394-398

Allergy Department, Hospital La Paz Institute for Health Research, Biomedical Research Network on Rare Diseases (CIBERER, U754), Madrid, Spain.

Background: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) causes swelling in the skin and upper airways and pain in the abdomen because of mucosal swelling. C1-INH-HAE is frequently misdiagnosed, leading to delays in diagnosis, inadequate treatment, and unnecessary procedures.

Objective: To evaluate the history of misdiagnosis in patients participating in the Icatibant Outcome Survey (IOS).

Methods: The IOS is an observational study in which safety and effectiveness of icatibant have been evaluated since 2009. As part of the IOS, patients record any misdiagnoses received before being diagnosed as having C1-INH-HAE.

Results: In January 2016, a total of 418 of 633 IOS patients with C1-INH-HAE type I or II had provided misdiagnosis data. Of these, 185 of 418 (44.3%) received 1 or more prior misdiagnoses. The most common misdiagnoses were allergic angioedema (103 of 185) and appendicitis (50 of 185). A variety of other misdiagnoses were reported, including a substantial number of gastrointestinal disorders (excluding appendicitis). Misdiagnosis rates were similar between males (41.1%) and females (46.5%) and between C1-INH-HAE type I (43.7%) and type II (51.6%). Patients with family members diagnosed as having C1-INH-HAE were significantly less likely to be misdiagnosed than patients without a family history (140 of 366 [41.7%] vs 38 of 58 [65.5%], respectively; P = .001). Patients with a prior misdiagnosis had longer median delay to C1-INH-HAE diagnosis (13.3 years) than patients without (1.7 years; P < .001).

Conclusion: From this large database, approximately 50% of patients with C1-INH-HAE type I or II have previously had their conditions misdiagnosed, most commonly as allergic angioedema or appendicitis. Misdiagnosis results in marked delays in receiving the correct diagnosis, during which time patients cannot access effective, lifesaving treatment.

Trial Registration: ClinicalTrials.gov: NCT01034969.
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http://dx.doi.org/10.1016/j.anai.2016.08.014DOI Listing
October 2016

Estimation of EuroQol 5-Dimensions health status utility values in hereditary angioedema.

Patient Prefer Adherence 2016 6;10:1699-707. Epub 2016 Sep 6.

Allergy Department, Hospital La Paz Institute for Health Research (IdiPaz), Biomedical Research Network on Rare Diseases U754 (CIBERER), University Hospital La Paz, Madrid, Spain.

Objective: To estimate health status utility (preference) weights for hereditary angioedema (HAE) during an attack and between attacks using data from the Hereditary Angioedema Burden of Illness Study in Europe (HAE-BOIS-Europe) survey. Utility measures quantitatively describe the net impact of a condition on a patient's life; a score of 0.0 reflects death and 1.0 reflects full health.

Study Design And Methods: The HAE-BOIS-Europe was a cross-sectional survey conducted in Spain, Germany, and Denmark to assess the real-world experience of HAE from the patient perspective. Survey items that overlapped conceptually with the EuroQol 5-Dimensions (EQ-5D) domains (pain/discomfort, mobility, self-care, usual activities, and anxiety/depression) were manually crosswalked to the corresponding UK population-based EQ-5D utility weights. EQ-5D utilities were computed for each respondent in the HAE-BOIS-Europe survey for acute attacks and between attacks.

Results: Overall, a total of 111 HAE-BOIS-Europe participants completed all selected survey items and thus allowed for computation of EQ-5D-based utilities. The mean utilities for an HAE attack and between attacks were 0.44 and 0.72, respectively. Utilities for an acute attack were dependent on the severity of pain of the last attack (0.61 for no pain or mild pain, 0.47 for moderate pain, and 0.08 for severe pain). There were no significant differences across countries. Mean utilities derived from the study approach compare sensibly with other disease states for both acute attacks and between attacks.

Conclusion: The impacts of HAE translate into substantial health status disutilities associated with acute attacks as well as between attacks, documenting that the detrimental effects of HAE are meaningful from the patient perspective. Results were consistent across countries with regard to pain severity and in comparison to similar disease states. The results can be used to raise awareness of HAE as a serious disease with wide-ranging personal and social impacts.
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http://dx.doi.org/10.2147/PPA.S100383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019462PMC
September 2016

Diagnostic screening of paroxysmal nocturnal hemoglobinuria: Prospective multicentric evaluation of the current medical indications.

Cytometry B Clin Cytom 2017 09 1;92(5):361-370. Epub 2016 Oct 1.

Cancer Research Centre (IBMCC, USAL-CSIC), Institute for Biomedical Research of Salamanca (IBSAL) and Department of Medicine and Cytometry Service (NUCLEUS Research Support Platform), University of Salamanca (USAL), Salamanca, Spain.

Background: Although consensus guidelines have been proposed in 2010 for the diagnostic screening of paroxysmal nocturnal hemoglobinuria (PNH) by flow cytometry (FCM), so far no study has investigated the efficiency of such medical indications in multicentric vs. reference laboratory settings.

Methods: Here we evaluate the efficiency of consensus medical indications for PNH testing in 3,938 peripheral blood samples submitted to FCM testing in 24 laboratories in Spain and one reference center in Brazil.

Results: Overall, diagnostic screening based on consensus medical indications was highly efficient (14% of PNH samples) both in the multicenter setting in Spain (10%) and the reference laboratory in Brazil (16%). The highest frequency of PNH cases was observed among patients screened because of bone marrow (BM) failure syndrome (33%), particularly among those with aplastic anemia (AA; 45%) and to a less extent also a myelodysplastic syndrome (MDS; 10%). Among the other individuals studied, the most efficient medical indications for PNH screening included: hemolytic anemia (19%), hemoglobinuria (48%) and unexplained cytopenias (9%). In contrast, only a minor fraction of the patients who had been submitted for PNH testing because of unexplained thrombosis in the absence of cytopenia, were positive (0.4%).

Conclusions: In summary, our results demonstrate that the current medical indications for PNH screening by FCM are highly efficient, although improved screening algorithms are needed for patients presenting with thrombosis and normal blood cell counts. © 2016 International Clinical Cytometry Society.
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http://dx.doi.org/10.1002/cyto.b.21480DOI Listing
September 2017

The Icatibant Outcome Survey: treatment of laryngeal angioedema attacks.

Eur J Emerg Med 2016 Jun;23(3):224-7

aDepartment of Immunology, Barts Health NHS TrustbDepartment of Dermatology and Venereology, Medical University of Graz, Graz, AustriacInternal Medicine Department, National Reference Centre for Angioedema, Grenoble University Hospital, Grenoble, FrancedAllergy Department, Hospital La Paz Institute for Health Research (IdiPaz), Biomedical Research Network on Rare Diseases (CIBERER, U754), Madrid, SpaineDepartment of Dermatology and Allergy, Allergie-Centrum-Charité, Charité - Universitätsmedizin Berlin, Berlin, GermanyfShire, Zug, SwitzerlandgDepartment of Biomedical and Clinical Sciences, University of Milan, Luigi Sacco Hospital, Milan, Italy.

Objective: To characterize the management and outcomes of life-threatening laryngeal attacks of hereditary angioedema (HAE) treated with icatibant in the observational Icatibant Outcome Survey (NCT01034969) registry.

Methods: This retrospective analysis was based on data from patients with HAE type I/II who received healthcare professional-administered or self-administered icatibant to treat laryngeal attacks between September 2008 and May 2013.

Results: Twenty centers in seven countries contributed data. Overall, 42 patients with HAE experienced 67 icatibant-treated laryngeal attacks. Icatibant was self-administered for 62.3% of attacks (healthcare professional-administered, 37.7%). One icatibant injection was used for 87.9% of attacks, with rescue or concomitant medication used for 9.0%. The median time to treatment was 2.0 h (n=31 attacks) and the median time to resolution was 6.0 h (n=35 attacks).

Conclusions: This analysis describes successful use of icatibant for the treatment of laryngeal HAE attacks in a real-world setting.
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http://dx.doi.org/10.1097/MEJ.0000000000000292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892758PMC
June 2016