An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial.

BACKGROUND: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. METHODS: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 × 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. FINDINGS: Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. INTERPRETATION: Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917). FUNDING: KalVista Pharmaceuticals.

[Skin reactions to the Pfizer-BioNTech vaccine for COVID-19. An Ecuadorian experience]. / Reacciones cutáneas a la vacuna Pfizer-BioNTech contra COVID-19. Una experiencia ecuatoriana.

OBJETIVE: To assess cutaneous reactions after Pfizer-BioNTech COVID-19 vaccine administration. METHODS: A cross-sectional observational study was carried out in health workers belonging to the city of Guayaquil-Ecuador, from March to May 2021. The participants were contacted through a local registry established by the Universidad Espíritu Santo. Frequencies and percentages were used to represent the proportions of nominal variables, while the mean and standard deviation were used for continuous data, given a normal sample distribution. RESULTS: Local skin reactions were the most frequent, and included redness, edema, and itching. On the other hand, delayed large local skin reactions (generalized rash and pruritus, angioedema, urticaria, eczema, petechiae) were rare and occurred in less than 1.4% of participants, (95% CI = 0.69-1.00). Finally, we did not find cases of anaphylaxis or other life-threatening reactions requiring urgent attention after vaccination. CONCLUSIONS: Our findings suggest that local skin reactions occur in a minority of recipients and are often mild and self-limited.

OBJECTIVO: Evaluar las reacciones cutáneas tras la administración de la vacuna COVID-19 de Pfizer-BioNTech. MÉTODOS: Se realizó un estudio observacional transversal en trabajadores de la salud, pertenecientes a la ciudad de Guayaquil-Ecuador, de marzo a mayo de 2021. Los participantes fueron contactados a través de un registro local establecido por la Universidad Espíritu Santo. Se utilizaron frecuencias y porcentajes para representar las proporciones de las variables nominales, mientras que la media y la desviación estándar se usaron para datos continuos, dada la distribución de muestra normal. RESULTADOS: Las reacciones cutáneas locales fueron las más frecuentes e incluyeron enrojecimiento, edema y prurito. Por otro lado, las reacciones cutáneas locales grandes retardadas (exantema y prurito generalizados, angioedema, urticaria, eccema y petequias) fueron raras y ocurrieron en menos de 1.4 % de los participantes, (IC 95 % = 0.69-1.00). Finalmente, no encontramos casos de anafilaxia u otras reacciones potencialmente mortales que requieran atención urgente después de la vacunación. CONCLUSIONES: Nuestros hallazgos sugieren que las reacciones cutáneas locales ocurren en una minoría de personas y que a menudo son leves y autolimitadas.

WAO-ARIA consensus on chronic cough - Part III: Management strategies in primary and cough-specialty care. Updates in COVID-19.

Background: Chronic cough management necessitates a clear integrated care pathway approach. Primary care physicians initially encounter the majority of chronic cough patients, yet their role in proper management can prove challenging due to limited access to advanced diagnostic testing. A multidisciplinary approach involving otolaryngologists and chest physicians, allergists, and gastroenterologists, among others, is central to the optimal diagnosis and treatment of conditions which underly or worsen cough. These include infectious and inflammatory, upper and lower airway pathologies, or gastro-esophageal reflux. Despite the wide armamentarium of ancillary testing conducted in cough multidisciplinary care, such management can improve cough but seldom resolves it completely. This can be due partly to the limited data on the role of tests (eg, spirometry, exhaled nitric oxide), as well as classical pharmacotherapy conducted in multidisciplinary specialties for chronic cough. Other important factors include presence of multiple concomitant cough trigger mechanisms and the central neuronal complexity of chronic cough. Subsequent management conducted by cough specialists aims at control of cough refractory to prior interventions and includes cough-specific behavioral counseling and pharmacotherapy with neuromodulators, among others. Preliminary data on the role of neuromodulators in a proof-of-concept manner are encouraging but lack strong evidence on efficacy and safety. Objectives: The World Allergy Organization (WAO)/Allergic Rhinitis and its Impact on Asthma (ARIA) Joint Committee on Chronic Cough reviewed the recent literature on management of chronic cough in primary, multidisciplinary, and cough-specialty care. Knowledge gaps in diagnostic testing, classical and neuromodulator pharmacotherapy, in addition to behavioral therapy of chronic cough were also analyzed. Outcomes: This third part of the WAO/ARIA consensus on chronic cough suggests a management algorithm of chronic cough in an integrated care pathway approach. Insights into the inherent limitations of multidisciplinary cough diagnostic testing, efficacy and safety of currently available antitussive pharmacotherapy, or the recently recognized behavioral therapy, can significantly improve the standards of care in patients with chronic cough.

Insights into urticaria in pediatric and adult populations and its management with fexofenadine hydrochloride.

OBJECTIVE: The present narrative review provides a comprehensive update of the current knowledge on urticaria, both in adult and pediatric populations, and on the safety and efficacy of fexofenadine hydrochloride (HCl) as a treatment option. DATA SOURCE: A literature search was conducted on Embase and Medline. STUDY SELECTION: Clinical studies published in English and published between 1999 and 2020 were selected. RESULTS: Although the exact pathogenesis of urticaria is not fully understood, multiple pathways of mast cell activation are discussed to explain the existence of phenotypically different clinical manifestations of urticaria. An overview of the worldwide prevalence of chronic urticaria, including disease burden and patient's quality of life is provided. The impact of urticaria on patient's life differs on the basis of whether its form is acute or chronic, but pharmacological approaches are most often needed to control the disabling symptoms. A summary of the current management of urticaria recommended by different guidelines across countries (Global; European; American; Australian; Asian; Japanese) is presented. Non-sedating, second-generation H1-antihistamines are the preferred choice of treatment across several guidelines worldwide. Herein, the efficacy and safety of fexofenadine HCl, a representative second-generation H1-antihistamine approved for the treatment of urticaria, is discussed. The occurrence of urticaria manifestations in COVID-19 patients is also briefly presented. CONCLUSION: The burden of acute and chronic urticaria is high for patients. Second generation anti-histamines such as fexofenadine HCl can help managing the symptoms.

The Role of Cetirizine in the Changing Landscape of IV Antihistamines: A Narrative Review.

Since 1955, the only available H1 antihistamines for intravenous administration have been first-generation formulations and, of those, only intravenously administered (IV) diphenhydramine is still approved in the USA. Orally administered cetirizine hydrochloride, a second-generation H1 antihistamine, has been safely used over-the-counter for many years. In 2019, IV cetirizine was approved for the treatment of acute urticaria. In light of this approval, this narrative review discusses the changing landscape of IV antihistamines for the treatment of histamine-mediated conditions. Specifically, IV antihistamines will be discussed as a treatment option for acute urticaria and angioedema, as premedication to prevent infusion reactions related to anticancer agents and other biologics, and as an adjunct treatment for anaphylaxis and other allergic reactions. Before the development of IV cetirizine, randomized controlled trials of IV antihistamines for these indications were lacking. Three randomized controlled trials have been conducted with IV cetirizine versus IV diphenhydramine in the ambulatory care setting. A phase 3 trial of IV cetirizine 10 mg versus IV diphenhydramine 50 mg was conducted in 262 adults who presented to the urgent care/emergency department with acute urticaria requiring antihistamines. For the primary efficacy endpoint, defined as change from baseline in a 2-h patient-rated pruritus score, non-inferiority of IV cetirizine to IV diphenhydramine was demonstrated (score - 1.6 vs - 1.5, respectively; 95% CI - 0.1, 0.3). Compared with IV diphenhydramine, IV cetirizine demonstrated fewer adverse effects including less sedation, a significantly shorter length of stay in the treatment center, and fewer returns to the treatment center at 24 and 48 h. Similar findings were demonstrated in another phase 2 acute urticaria trial and in a phase 2 trial assessing IV cetirizine for pretreatment for infusion reactions in the oncology/immunology setting. IV cetirizine is associated with similar patient outcomes, fewer adverse effects, and increased treatment center efficiency than IV diphenhydramine.

Cannabis-related allergies: An international overview and consensus recommendations.

Cannabis is the most widely used recreational drug in the world. Cannabis sativa and Cannabis indica have been selectively bred to develop their psychoactive properties. The increasing use in many countries has been accelerated by the COVID-19 pandemic. Cannabis can provoke both type 1 and type 4 allergic reactions. Officially recognized allergens include a pathogenesis-related class 10 allergen, profilin, and a nonspecific lipid transfer protein. Other allergens may also be relevant, and recognition of allergens may vary between countries and continents. Cannabis also has the potential to provoke allergic cross-reactions to plant foods. Since cannabis is an illegal substance in many countries, research has been hampered, leading to challenges in diagnosis since no commercial extracts are available for testing. Even in countries such as Canada, where cannabis is legalized, diagnosis may rely solely on the purchase of cannabis for prick-to-prick skin tests. Management consists of avoidance, with legal issues hindering the development of other treatments such as immunotherapy. Education of healthcare professionals is similarly lacking. This review aimed to summarize the current status of cannabis allergy and proposes recommendations for the future management of this global issue.

Contact dermatitis due to personal protective equipment use and hygiene practices during the COVID-19 pandemic: A systematic review of case reports.

BACKGROUND: Prolonged use of personal protective equipment (PPE) may lead to contact dermatitis during the coronavirus disease 19 (COVID-19) pandemic. This paper aims to identify the causative factors of contact dermatitis from PPE and hygiene practices. METHODS: The search was conducted adhering to PRISMA 2020 guidelines. A Delphi process was employed to ensure that the aims of this study were met. PubMed and Web of Science databases were systematically searched through September 12, 2021, using search terms: Contact dermatitis, case report, covid-19. The findings were tabulated as author/year, gender, age, presentation, cause, dermatological diagnosis, testing modality, provided treatment, symptom resolution (time in days), prognosis, and follow-up. RESULTS: The mean age of all individuals was 29.75 years, with 75% females. All cases presented with erythema, with 62.5% reporting pruritus and 37.5% reporting burning facial symptoms. Surgical masks and hand-hygiene products (37.5%) were the most commonly reported causative agent with 25% due to KN95/FFP type 2 use. Allergic contact dermatitis (50%) and irritant contact dermatitis (25%) were common diagnoses. Treatments included creams, emollients, and desloratadine, with restriction of irritant-causing factors. The prognosis was generally good among the cases, with 62.5% presenting complete resolution within a week and 12.5% showing moderate improvement at the fourth month after discontinuing use. CONCLUSION: This study finds pertinent links between PPE use and contact dermatitis during the COVID-19 pandemic. While many cases are bound to go underreported in literature, well-designed, large-scale studies in the future may help promote these associations in a more comprehensive manner.

WAO-ARIA consensus on chronic cough - Part II: Phenotypes and mechanisms of abnormal cough presentation - Updates in COVID-19.

BACKGROUND: Chronic cough can be triggered by respiratory and non-respiratory tract illnesses originating mainly from the upper and lower airways, and the GI tract (ie, reflux). Recent findings suggest it can also be a prominent feature in obstructive sleep apnea (OSA), laryngeal hyperresponsiveness, and COVID-19. The classification of chronic cough is constantly updated but lacks clear definition. Epidemiological data on the prevalence of chronic cough are informative but highly variable. The underlying mechanism of chronic cough is a neurogenic inflammation of the cough reflex which becomes hypersensitive, thus the term hypersensitive cough reflex (HCR). A current challenge is to decipher how various infectious and inflammatory airway diseases and esophageal reflux, among others, modulate HCR. OBJECTIVES: The World Allergy Organization/Allergic Rhinitis and its Impact on Asthma (WAO/ARIA) Joint Committee on Chronic Cough reviewed the current literature on classification, epidemiology, presenting features, and mechanistic pathways of chronic cough in airway- and reflux-related cough phenotypes, OSA, and COVID-19. The interplay of cough reflex sensitivity with other pathogenic mechanisms inherent to airway and reflux-related inflammatory conditions was also analyzed. OUTCOMES: Currently, it is difficult to clearly ascertain true prevalence rates in epidemiological studies of chronic cough phenotypes. This is likely due to lack of standardized objective measures needed for cough classification and frequent coexistence of multi-organ cough origins. Notwithstanding, we emphasize the important role of HCR as a mechanistic trigger in airway- and reflux-related cough phenotypes. Other concomitant mechanisms can also modulate HCR, including type2/Th1/Th2 inflammation, presence or absence of deep inspiration-bronchoprotective reflex (lower airways), tissue remodeling, and likely cough plasticity, among others.

Needs assessment: knowledge of self-management of asthma for children with co-morbid physical and intellectual disabilities: brief report.

OBJECTIVES: The main goal of this study was to conduct a needs assessment to ascertain professionals' and parents' knowledge of and perceptions about education for self-management of asthma for children with physical and intellectual disabilities (IDs). Another goal was to understand needs for education of children with IDs about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; coronavirus) and other infectious diseases. METHODS: Surveys, presented in the RedCap system, were administered online. Respondents (n = 498) were recruited through sites and listservs for children with disabilities and individuals with asthma. Respondents answered eight questions about knowledge and education for self-management of asthma for children with physical disabilities and IDs. Respondents answered four questions pertaining to management of coronavirus for children with IDs. RESULTS: Respondents' indicated that it would be easier to educate youth with mild or moderate versus severe levels of disabilities. Children with IDs may not receive the education they need to manage their asthma. When comparing those in different occupations, teachers reported lower knowledge for educating children with IDs about asthma management and coronavirus. CONCLUSIONS: Doctors and nurses can develop programs for children with physical disabilities and IDs. Programming for youth with severe impairments is needed and perhaps developmentally appropriate programming for youth with IDs will improve education of youth and, concomitantly improve their self-management of asthma and potentially quality of life. Educating teachers is critical specifically about asthma triggers, how to involve youth in self-care, and how to educate children with IDs about coronavirus.Abbreviations:U.S.: United States;IDs: intellectual disabilities.

Atopic endotypes as a modulating factor for SARS-CoV-2 infection: mechanisms and implications.

PURPOSE OF REVIEW: Asthma patients are typically at increased risk for severe outcomes from viral respiratory infections. However, asthma and atopy do not appear to be overrepresented comorbidities in COVID-19 patients, and hypotheses attempt to explain this observation. As COVID-19 continues to spread globally, it is imperative to understand how disease outcomes may be influenced in this population to guide patient care. RECENT FINDINGS: Angiotensin converting enzyme 2 (ACE2) is the principal host cell receptor for SARS-CoV-2 entry and Transmembrane Protease Serine 2 (TMRSS2) is the main priming protease. Models have linked atopic endotypes to reductions in ACE2 and increases in TMRSS2 on respiratory epithelia. Epidemiologic and experimental findings imply alterations in ACE2 expression correlate with clinical COVID-19 disease, but limitations restrict the ability to draw direct conclusions. SUMMARY: There is reasonable evidence to assert atopic endotypes modulate COVID-19 susceptibility, but it remains premature to classify this association as protective or deleterious. Asthma is a heterogeneous disease and epidemiologic studies should focus on investigating COVID-19 outcomes by underlying endotype. Direct experimental and clinical evidence is needed to draw definitive conclusions on how the complex interplay of ACE2 and TMRSS2 affect viral entry. VIDEO ABSTRACT: https://www.dropbox.com/sh/9sfwqhz2h78sio3/AAB0JYd4MFzM5JjDFcYwz4CXa?dl=0.

"It seems like COVID-19 now is the only disease present on Earth": living with a rare or undiagnosed disease during the COVID-19 pandemic.

PURPOSE: Patients with rare and undiagnosed diseases (RUDs) face significant health challenges, which may be exacerbated during the COVID-19 pandemic. The goal of this study was to identify specific impacts of the pandemic on RUD patients, and targets for improving support and health-care access. METHODS: We conducted an online survey of RUD patients and their family members from 21 April to 8 June 2020, recruited from 76 Facebook groups for RUDs. Questions assessed patient characteristics and impacts of the pandemic on RUD diagnosis and management. RESULTS: Respondents (n = 413), including 274 RUD patients and 139 family members, were predominantly female and white, though income varied. Impacts of the pandemic included (1) barriers to accessing essential health care, (2) specific impacts of restrictive COVID-19 visitation policies on ability to advocate in health-care settings, (3) uncertainty and fear regarding COVID-19 risk, (4) exacerbated physical and mental health challenges, (5) magnified impacts of reduced educational and therapeutic services, and (6) unexpected positive changes due to the pandemic. CONCLUSION: There are specific, serious challenges affecting RUD patients and families during the COVID-19 pandemic. There is an urgent need to develop approaches to mitigate these challenges both during and beyond the pandemic.

The global impact of the COVID-19 pandemic on the management and course of chronic urticaria.

INTRODUCTION: The COVID-19 pandemic dramatically disrupts health care around the globe. The impact of the pandemic on chronic urticaria (CU) and its management are largely unknown. AIM: To understand how CU patients are affected by the COVID-19 pandemic; how specialists alter CU patient management; and the course of CU in patients with COVID-19. MATERIALS AND METHODS: Our cross-sectional, international, questionnaire-based, multicenter UCARE COVID-CU study assessed the impact of the pandemic on patient consultations, remote treatment, changes in medications, and clinical consequences. RESULTS: The COVID-19 pandemic severely impairs CU patient care, with less than 50% of the weekly numbers of patients treated as compared to before the pandemic. Reduced patient referrals and clinic hours were the major reasons. Almost half of responding UCARE physicians were involved in COVID-19 patient care, which negatively impacted on the care of urticaria patients. The rate of face-to-face consultations decreased by 62%, from 90% to less than half, whereas the rate of remote consultations increased by more than 600%, from one in 10 to more than two thirds. Cyclosporine and systemic corticosteroids, but not antihistamines or omalizumab, are used less during the pandemic. CU does not affect the course of COVID-19, but COVID-19 results in CU exacerbation in one of three patients, with higher rates in patients with severe COVID-19. CONCLUSIONS: The COVID-19 pandemic brings major changes and challenges for CU patients and their physicians. The long-term consequences of these changes, especially the increased use of remote consultations, require careful evaluation.

COVID-19, asthma, and biologic therapies: What we need to know

Managing patients with severe asthma during the coronavirus pandemic COVID-19 is a challenge. Authorities and physicians are still learning how COVID-19 affects people with underlying diseases, and severe asthma is not an exception. Unless relevant data emerges that changes our understanding of the relative safety of medications indicated in patients with asthma during this pandemic, clinicians must follow the recommendations of current evidence-based guidelines, preventing loss of control and exacerbations. Also, with the absence of data that would indicate any potential harm, current advice is to continue the administration of biologic agents during the COVID-19 pandemic in patients with asthma for whom such agents are clearly indicated and have been effective. For the patients with severe asthma infected by SARS-CoV-2, the decision to maintain or postpone biologic therapy until the patient recovers should be a case-by-case based decision supported by a multidisciplinary team. A registry of cases of COVID-19 in patients with severe asthma, including those treated with biologics, will help to address a clinical challenge where we have more questions than answers.