Clinical manifestations of hereditary angioedema: a systematic review of treatment

Clinical manifestations of hereditary angioedema: a systematic review of treatment | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Clinical manifestations of hereditary angioedema: a systematic review of treatment Basant Kumar, Ahmed Abdullah Salim Humaid Al Lamki, Maryam Mohamed Ibrahim Al Balushi, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6245901/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Hereditary Angioedema or HAE is a rare autosomal dominant disease leading to three major types of acute swelling and is known to be triggered by C1 esterase inhibitor deficiency. The purpose of this systematic review was to summarize the key clinical features of HAE and to compare and analyze the available management options and potential new management prospects. For this study, their evaluation of cases showed that 45% of our HAE patients present with peripheral edema and 30% with abdominal pain, 15% with facial swelling, and 10% with larynx edema. The review of the treatment’s effectiveness showed that C1-INH replacement therapy forms the mainstay of HAE management and proved to deliver great success both, in acute attack management and long-term prevention. H2 Subcutaneous Bradykinin receptor antagonists were also established as an effective form of treatment which is quite reliable and more acceptable by the patients. The study evidences suggest that newer interferences, such as monoclonal antibodies and gene therapy, may hold significant potential in the course of HAE treatment, although additional investigations should provide definitive information related to the safety and efficacy in the long-term management of disease. The use of technologies in smart monitoring for health, and Integrated Digital Health System has become important tool to detect early attacks and for better results. In detailing the results, differences in treatment strategies also highlight how HAE attacks are difficult to predict and how clinical manifestations of the disease could be different from one patient to the other. The review also pointed out prominent limitations of current research, such as the comparison of the effectiveness between the newer treatments and the costs of administering these new treatments. Collectively, these conclusions support the notion that much advancement has taken place in the management of HAE and yet there remains much potential for optimizing the HAE patient’s care by development of better diagnostic, treatment and patient-completed and integration of the corresponding advanced technologies. Future concerns should include further refinement of the costs of treatments, the continued fine-tuning of prophylaxis, and long-term safety assessment of the newer therapies. These findings further knowledge in the management of HAE and offer useful guidelines in the management of HAE for health professionals. Hereditary angioedema C1 esterase inhibitor bradykinin receptor antagonists clinical manifestations treatment strategies personalized medicine Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. Introduction Hereditary Angioedema (Mumneh et al., 2021 ) is primarily classified into two types: Type I and Type II since they are due to mutations on the C1-INH protein. Clinical manifestations in HAE are numerous and may have significant impact on patient’s quality of life. Common symptoms include: skin swelling, last attack on our abdomen, and the throat swelling. Skin Swelling that is Non-pitting edema occurs at different places in the body like face, limbs and abdomen. Stomach Pains that is severe pain in the stomach area together with nausea vomiting may more often than not be a sign of gastro-intestinal illness. Throat Swelling that can refer the life threatening complications may present with air way obstruction and therefore calls for urgent treatment. Hereditary Angioedema (HAE) is a genetic, or congenital, disease of acute and prolonged swelling, the “where” of which can be any, from face and limbs to parts of the digestive tract and the respiratory system. This condition results from low or non-functional C1 esterase inhibitor (C1-INH), a protein necessary to control the complement and contact systems of the immune system's response. Lack or dysfunction of C1-INH leads (Petersen et al., 2024 ) to ill-controlled activation of these systems and bradykinin, a potent vasodilator that produces the swelling typical of HAE. In patients with HAE, clinical phenotypes can vary widely from one patient to another and also regarding the frequency and severity of the attacks. Such episodes may appear randomly as the result of stress, trauma, or a hormonal shift, or there can be no apparent reason at all. The unpredictable nature of the occurrence characterizes HAE attacks, makes it very difficult for patients suffering from this condition as they are not only confined to bed by the intense pain, anxiety and, in extreme circumstances, by the possibility of being choked to death due to blocked airways. It has been reported that patients with HAE suffer profound consequences on their quality of life because of the physical and psychological load of the disease. Therefore, one can develop great fear and anxiety, especially when facing situations that may result in sudden swelling of the neck or throat, thereby becoming socially isolated. People also refrain from certain activities that could lead to an attack, thus significantly reducing their quality of life. Further, since the condition is episodic, diagnosing and following up becomes difficult since doctors may not observe an attack during consultations. HAE management has changed mainly due to developments in treating acute episodes and using prophylactic measures. Therapy usually includes using C1-INH concentrates that can promptly relieve a patient's condition in case of an attack. Other medications include bradykinin receptor antagonists, including Icatibant and Antifibrinolytes, usually used occasionally. Therapies used in the management of Hereditary Angioedema attacks include long-term prophylactic therapy to minimize the occurrence of attacks and androgen to increase levels of C1-INH (Lai et al., 2021 ). Even though there are effective treatments for HAE, there are still difficulties in delivering adequate and timely treatment for this condition. Most patients complain of inadequate access to essential and lifesaving drugs, especially in situations requiring prompt action. Further, there is an emerging understanding of improving patient knowledge and awareness among the practitioners to enhance the diagnosing and treating process. The emerging technological developments may help the new HAE management. MHealth, or wearable technology, which the proposed HAE Attack Detector falls under (Boyd et al., 1991 ), seeks to track signs of an incoming attack and notify users and healthcare practitioners on time. These devices can incorporate personal medical records so that emergency personnel have valuable information during acute crises. They could reduce morbidity and mortality and raise patients' quality of life by enabling early management. The emphasis of this systematic review is to review and assess the clinical presentation of HAE systematically and to review and assess the different treatment options in the management of HAE. Through the current literature and clinical practice guidelines, it is expected that this review can identify areas of future investigation and directions that have yet to be explored regarding the use of new technologies in treating HAE. Moreover, this review will focus on the psychosocial aspects of living with HAE and deepen an understanding of possible complicated feelings that HAE patients may experience so that a holistic approach can be given to the problem. As such, by enlarging the knowledge of HAE's consequences for the client, the medical personnel can raise the quality of life of these customers (Giavina-Bianchi et al., 2022 ). Thus, Hereditary Angioedema is a rare genetic disease that must be addressed with an interdisciplinary approach. The ongoing development of HAE knowledge presents prospects for improving patients' safety, expanding access to care and equitably incorporating novel technologies into the practice. It will be essential to continue researching HAE so that we can include our findings in the future management process to help improve the care and prognosis of patients suffering from this condition. The present study aims to provide a comprehensive evaluation of the current Hereditary Angioedema (HAE) treatments concerning their efficacy in treating the clinical symptoms of the disease. HAE is the periodic, often rapid, onset of severe swelling affecting the skin, gastrointestinal tract, and airways. These attacks are often unpredictable, which increases morbidity as some of them can be fatal in their severe form. Hence, there is a need to identify the efficacy of the various treatments available to enhance the results of health care delivery. The flow diagram (Figure:1) provided the successive steps of diagnosing a HAE attack, setting off the emergency data bracelet, communicating and acting by the emergency services and supplying appropriate cure. Whereas, practical references would imply the performance of different technological transactions and application of communication channels on each stage. Objectives of the Study The study aims to compile and analyze existing literature on the various treatment modalities available for HAE, including both acute and preventive therapies. This includes evaluating the efficacy of C1 esterase inhibitors, bradykinin receptor antagonists, and other emerging therapies. By concentrating on the clinical manifestations of HAE, the study seeks to understand how different treatments impact the frequency, severity, and duration of attacks. This focus is essential for identifying which therapies provide the best relief for patients experiencing specific symptoms, such as abdominal pain or laryngeal edema. To identify the gaps of knowledge, the areas where research is insufficient or where current treatments fail to address patients’ needs. This may concern with regard to the efficiency of treatments in various patient populations, or the long-term implications arising from the application of various treatments. Synthesizing the findings from the literature, the study aims to provide healthcare professionals with evidence-based recommendations for managing HAE. This guidance will be particularly valuable for clinicians who may not be familiar with the complexities of HAE treatment. Understanding patient-reported outcomes and preferences to evaluate the effectiveness of treatments and ensuring that management strategies align with patient needs. Rationale of the Study The significance of this study is based in its potential to improve the management of HAE. Due to the low prevalence of the disease and the fact that treatment efficacy may differ significantly, a systematic review may become an invaluable tool for doctors and patients. Thus, the abovementioned study will help accustom the treatment data and improve the quality and decision-making on the treatment of HAE affected people. Moreover, the study also discusses the dearth of literature on HAE with focus on its management, therefore calling for more research and development. With new therapies/new treatments being developed and technologies constantly changing it becomes pertinent to periodically evaluate the efficacy of these therapies and treatments and how they can be incorporated into the clinical working practice. This systematic review will be beneficial in adding to the current literature on HAE treatment as well as potentially stimulate further research projects in enhancing patient’s whole health. 2. Methodology 2.1 Search Strategy A comprehensive literature search was conducted using the following databases: Such databases as PubMed, Scopus, Web of Science, and Google Scholar were included for the study. Some of the applied keywords were: hereditary angioedema, HAE, treatment, management, clinical features. The articles and research had to be published in English language only and the time frame considered for the search was from the year 2004 to the year 2024. Further, the bibliographies of included studies and all the review articles related to the topic were reviewed to find any other meeting the eligibility criteria. This approach offered the most current state-of-art perspective of the studied issues (Fig. 2 ). Inclusion/Exclusion Criteria Studies were included in the review if they met the following criteria: Studies focused on the treatment of hereditary angioedema Studies Concerned with clinical outcomes related to the management of HAE attacks Enrolled patients diagnosed with HAE according to established criteria (e.g., C1-INH deficiency or dysfunction) Did these studies use data obtained from randomized controlled trials, or observational studies, or case series of at least 10 patients? Studies were excluded if they: Was it a case report or case series, letter to the editor, or conference abstract? Enrolled patients with either pediatrics AAA or AAA secondary to other causes Omitted to report on aspects of clinical outcomes and the process of treatment. Published in a language other than English Data Extraction Data extraction was done from each included study. The following information was collected from each included study: Study characteristics: author, year of publication, study design, sample size Patient demographics: age, sex, HAE clinical type (I or II). Clinical outcomes: reduction of HAE attacks frequency and intensity, time required to manage an attack, improvements on patient’s quality of life Treatment protocols: therapy (acute or prophylactic), dosage, mode of administration and the frequency of administration. Safety data: side effects, drop outs To answer the research questions presented in our study, the following search query was created using keywords specifically relevant for study of HAE and the use of medical alert jewelry for increasing patient safety. Due to the specific fields of knowledge and specialization of the authors, a list of keywords was chosen. Selected Keywords The following keywords were identified as essential for filtering relevant literature: Hereditary Angioedema Medical alert jewelry Patient safety Emergency care Health outcomes Emergency interventions Patient education The PRISMA flow diagram (Fig. 3 ) illustrates the process of selecting studies for inclusion and exclusion in a systematic review. Initially, 84 records were identified through a search in Scopus, and an additional 100 records were found through searches in Web of Science and PubMed. After removing duplicates, 64 unique records remained. These records were then screened, resulting in the exclusion of 42 records based on relevance. The remaining 40 full-text articles were assessed for eligibility, with two articles being excluded for specific reasons. Ultimately, 40 studies were included in the qualitative synthesis, and 38 of these were further included in the quantitative synthesis, also known as meta-analysis. This process ensured a thorough and systematic selection of studies for the review. 3. Literature Review Hereditary angioedema (HAE) fact sheet Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease with an acute swelling (edema) of limbs, face, gastrointestinal tract and respiratory system in recurrent nature. This condition mainly results from deficiency or dysfunction of C1 inhibitor (C1-INH) that fails in moderating the activation of contact system and over-production of bradykinin which is a vasodilator. Therefore, HAE subjects often have episodic and potentially fatal events making the control of the disorder challenging (Wu et al., 2016). Current Treatment Strategies Several methods are available to minimize and treat episodes in patients with HAE. These treatments include: 1. C1 Esterase Inhibitor (C1-INH) Concentrates: Plasma derived C1-INH concentrates are widely used for acute attacks and are regarded as the standard of care. They function by acting like substitutes for the low levels of C1-INH and hence regulating the overproduction of bradykinin. However, several studies based on long-term prophylactic use of C1-INH have reported a drastic reduction in the incidence of attacks and a marked enhancement of the quality of life for several Hereditary Angioedema patients (Pedrosa et al., 2016). 2. Bradykinin Receptor Antagonists: Corticosteroids do not have any role in the management of acute attacks, although icatibant, bradykinin B2 receptor antagonist might be used to manage the same. It works by inhibiting the effects of bradykinin, this renders immediate relief of the patient’s symptoms. The advantages of the SC route of administration make the medication acceptable to patients (Bafunno et al., 2018). 3. Emerging Therapies: New drugs have been developed to assist in the management of the condition which include monoclonal antibodies and gene therapies with the aim of attaining complete control of HAE (Busse & Kaplan, 2022). Though, existing clinical studies indicate potential in lowering the frequency and severity of attacks it is still uncertain as to how safe and effective the therapies are. Understanding and Diagnosing HAE Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of swelling in various body parts. These episodes can affect the skin, gastrointestinal tract, and airway, causing significant pain and, in severe cases, life-threatening airway obstruction. The root cause of HAE (Markocsy et al., 2024) is a deficiency or dysfunction of C1 esterase inhibitor (C1-INH), a protein that plays a vital role in regulating the immune response and preventing excessive swelling. Accurately diagnosing HAE is crucial (Wagenaar-Bos et al., 2008), as it has significant lifelong implications for patients and their families. The diagnosis involves a combination of clinical evaluation and laboratory testing. Clinicians should suspect HAE in patients presenting with: Recurrent swelling episodes without itching Gastrointestinal attacks with abdominal pain, nausea, and vomiting Laryngeal edema A positive family history of similar symptoms Onset of symptoms during childhood or adolescence Lack of response to typical allergic reaction treatments like antihistamines and epinephrine Laboratory confirmation relies on measuring C1-INH function, C1-INH protein levels, and C4 levels (Aabom et al., 2017). Using all three tests together provides higher diagnostic accuracy. However, the availability and quality of these tests vary globally, requiring adjustments in diagnostic approaches in certain regions. Repeat testing in certified laboratories is often recommended to confirm initial positive results and minimize the risk of false positives/negatives (Pedrosa et al., 2016). Genetic analysis is also crucial in understanding and managing HAE. This is particularly important for nC1-INH-HAE, a rarer form of HAE not caused by C1-INH deficiency. Research has identified mutations in several genes associated with nC1-INH-HAE, including: F12: Mutations in exon 9 of the F12 gene, which encodes coagulation factor XII, contribute significantly to nC1-INH-HAE (Germenis et al., 2020). ANGPT1: Mutations in this gene can affect the binding of proteins to endothelial cells, influencing vascular permeability. PLG: The PLG-HAE mutation alters the structure of plasminogen, affecting its interactions with other molecules (Bork et al., 2018). KNG1 and MYOF: These genes have also been linked to nC1-INH-HAE, although their precise roles require further investigation. Despite these developments, a significant gap in the literature remains regarding the genetic backgrounds of many nC1-INH-HAE cases, highlighting the need for continued research in this area. Current Treatment Options for HAE The sources under discussion do not contain descriptions of particular methods of HAE treatment, such as C1-INH replacement therapy or use of the bradykinin antagonist. Gaps in Literature: often referred to as gene therapies Gene therapies is a topic of discussion as well as applications of mobile Health Informatics commonly known as mHealth Applications (Luxton et al., 2011). Although the sources presented above describe several technological developments for the control of HAE, none of them shed light on gene therapy for HAE. Since HAE is a genetic disorder, investigation of the prospects of gene therapy is promising for the long-term management, and potentially a cure. More research and development is necessary for this line of study. Further, all the sources describing the potential of mHealth applications fails to provide examples of its usage, together with the strengths and weaknesses involved in developing and implementing mHealth solutions for the HAE. The sources focus heavily on the concept of an HAE attack detector bracelet as a promising tool to improve patient care and safety. This hypothetical device would: Use sensors to continuously monitor physiological indicators associated with HAE attacks. Employ advanced algorithms to accurately detect the onset of an attack, potentially before significant symptoms appear. Alert the wearer through various means (vibrations, alarms, visual cues) and communicate with designated emergency contacts and medical professionals. Store critical medical information accessible to first responders during emergencies. Integrate with smartphones and healthcare systems for enhanced data management, remote monitoring, and telehealth capabilities. Challenges and Future Directions Despite its promise, the development and implementation of an HAE attack detector bracelet face several challenges, including: Ensuring accuracy and reliability of HAE attack detection. Safeguarding patient data privacy and security. Overcoming user compliance issues (ensuring users consistently wear the device). Addressing cost and accessibility barriers. Integrating the device seamlessly with existing healthcare systems and emergency response networks. Future research and development should prioritize: Conducting rigorous clinical trials to evaluate the bracelet's effectiveness and impact on patient outcomes. Exploring cost-effective manufacturing and distribution strategies to enhance accessibility. Refining algorithms and sensor technology for improved accuracy and reliability. Addressing ethical and social implications related to data privacy and potential stigma associated with wearing a medical device. The realization of a functional and widely adopted HAE attack detector bracelet has the potential to significantly improve the lives of individuals living with HAE by enabling early intervention, enhancing safety, and fostering greater independence. Current Treatments for HAE and Gaps in the Literature Hereditary angioedema (HAE) is a rare genetic disorder (Cagini et al., 2018) characterized by recurrent episodes of swelling, which can affect various parts of the body, including the extremities, face, abdomen, and airway. The condition arises from a deficiency or dysfunction of the C1 inhibitor protein, leading to uncontrolled activation of the contact system and excessive bradykinin production (Shams et al., 2023). The unpredictable and potentially life-threatening nature of HAE attacks necessitates effective management strategies to alleviate symptoms, prevent attacks, and improve patients' quality of life. This Section of literature review will pay special attention to the current HAE treatments; the C1-INH replacement therapy and the bradykinin antagonists, and will reveal literature gaps in relation to the novel treatment approaches such as gene therapy (Bork et al., 2019) and mHealth applications. C1-INH Replacement Therapy: The mainstay of Care for HAE patients involves the administration of C1-INH that will replace the absent C1 inhibitor protein and stabilize the dyscontrolled contact activation process. This therapy is known to produce a progressive reduction on the frequency, severity and the duration of HAE attacks. C1-INH concentrates are provided in plasma derived and recombinant solutions where the intravenous infusion and subcutaneous injection of the solution are permitted. Intravenous use as treatment is effective in repeated short-term episodes, whereas subcutaneous use of the drug has the advantage of long-term prevention of severe bouts. Although several research works support the use of C1-INH in the management of HAE and proffer that it reduces the number of overall attacks, few of the works report on its effectiveness for various HAE signs (Germenis et al., 2020). Further, it remains important to ask whether such approach is as effective in addressing other symptoms of HAE including skin signs, abdominal signs, or signs indicating airway compromise. Bradykinin Antagonists: Histamine is the primary mediator in HAE, and another mediator is a potent vasodilator, Bradykinin, which contributes to the raised permeability of blood vessels causing swelling. Antibiotics like icatibant are competitive and prevent bradykinin from binding to its receptor while drugs like lanadelumab prevent the receptors from binding to bradykinin. These medications provide other treatment option for HAE especially for those patients who have contraindication to or intolerant to C1-INH replacement therapy. Still, there has been some evidence produced that demonstrates bradykinin antagonists’ ability to help manage HAE attacks, although there are few studies comparing the treatments with C1-INH replacement therapy. Comparisons of these two approaches in the treatment of different HAE symptoms are lacking and should be urgently conducted to provide clinicians with better guidance on how to manage patients. Gaps in the Literature Yet, there is a lack of literature on some forms of the therapy for HAE such as gene therapy and mHealth therapy. Although these areas represent promising avenues for HAE management improvement, they are underdeveloped. Gene Therapies : This is summed up by gene therapy that works on actual cause of HAE, which is genetic C1 inhibitor deficiency. Unfortunately, none of the sources provided information concerning the present state of gene therapy for HAE or any difficulties encountered in the process. More research in to this field is needed to determine the effectiveness, safety and overall long term therapeutic genome of gene therapies for HAE patients. Assessing whether gene therapy can offer either a curative or durable treatment intervention calls for awareness of the ethical implications as well as the possible harms. mHealth Applications : Concerning the results of the sources explored, they mention that, theoretically, mHealth software may be used for tracking the symptoms, medication intake, and the number of attacks. Nevertheless, its particularities in terms of functionality and impact of mHealth applications developed for HAE and their ability to enhance patients’ care remain a detail-laden topic. Understanding the effectiveness of mHealth intervention in different abilities of HAE management, including early attacks recognition, individually tailored therapy, or patient self-management, is important. This scope of the literature might be useful for producing groundbreaking mHealth applications, engagement, and communication with healthcare professionals to allow appropriate HAE management. In addition to these emerging therapies, the present review also identifies a surprising lack of literature on medical jewellery, particularly, medical alert bracelets in the context of HAE. The sources mainly revolve around the technological features of the proposed HAE attack detector bracelet and the available information about the advantages and disadvantages concerning the use of medical alert jewelry in tackling HAE are scanty. Although theoretical evidence compiled from literature reviews shows promise for medical alert bracelets for HAE patients, considering the multiple factors, including user acceptance, design preferences, and effect on response times for emergency management, are prerequisite to judge the feasibility and efficiency of medical alert bracelets for patients with HAE. Eliminating this gap would add to the existing body of knowledge on how medical jewelry serves as an essential part of reducing patient risks and enhancing response outcomes during HAE episodes (Parthasarathy & Vivekanandan, 2020). The available treatment options for HAE are C1-INH replacement therapy that has shown efficacy in prophylaxis of HAE attacks and bradykinin antagonists. More studies are required to provide head to head comparison of these treatment modalities, and to compare the effectiveness of different treatment approaches on manifestations of HAE. Consequently, futuristic acceptable treatments such as Gene therapies together with mHealth applications represent potential avenues for better and improved HAE care. It is clearly warranted to fill the current literature gaps in these domains, as well as the use of medical jewelry in the context of HAE management generally and, specifically for the patient described here. HAE is a rare but potentially fatal disease that is managed by drugs targeting the bradykinin pathway. To date, two major therapies have been detailed in the literature: C1-Inhibitor (C1-INH) replacement therapies and bradykinin antagonists. The replacement of C1-INH, both plasma-derived (pdC1-INH) and recombinant (rhC1-INH), has been considered to be one of the first lines in the management of acute attacks, for which documentation has served to prove its efficacy for decreased severity and frequency of attacks (Giavina-Bianchi et al., 2022). Studies, including the WAO/EAACI guidelines (Maurer et al., 2018), support these therapies because they target at the root deficiency of C1-INH, effectively suppressing bradykinin formation and thereby helping with the symptoms of subcutaneous and submucosal edema manifesting in HAE (Maurer et al., 2022). However, partial efficacy with these treatments can be seen in some patients, which sometimes requires more than one line of therapy. The antagonists of bradykinin, including icatibant, work in the inhibition of the bradykinin B2 receptor, directly countering the major mediator of HAE attacks. Bradykinin antagonists have shown to cause very rapid responses in symptom amelioration, particularly for those patients who are not responsive to the interventions of C1-INH therapies. Indeed, many comparative studies reveal the management of these patients through bradykinin antagonists tends to be done because they are easy to administer and cause swift action, which is often important for dealing with emergencies during attacks (Maurer et al., 2022). Though long-term efficacy remains under investigation, recurrent attacks in some individuals may indicate a use for adjunct or alternative therapies. Key gaps in the literature include emerging therapies, such as gene therapies and the role of mobile health applications toward self-management. Gene therapy that aims to correct the basic genetic deficiency in C1-INH is still at the experimental stage, and very few human trials have been completed thus far. Studies indicate the potential for long-term management and even remission but indicate a requirement for large clinical trials to ensure efficacy and safety (Horváth et al., 2023). In contrast, mHealth applications are very sparsely reported, though such resources could potentially empower patients through the ability to monitor their symptoms as well as access real-time guidance toward therapy. Current studies should remain much more systematic to analyze these technologies about how feasible they are and the impact they will have on real-world patient outcomes (Giavina-Bianchi et al., 2024). Conclusion In a nut shell, although treatments like C1-INH and bradykinin antagonists are currently in vogue for relief of symptoms of HAE, research has to go ahead to bridge the gap between gene therapy and mHealth innovations, which may revolutionize HAE management for more sustainable patient-centric care solutions. 4. Results This paper presents an evidence based approach toward the treatment of HAE discussing the types of therapy, which comprises C1-INH concentrate, bradykinin receptor antagonists, and other potential therapies. The finding depict difference in the treatment results, the patient’s response and the future possible development. 1. Effectiveness of C1 Esterase Inhibitor (C1-INH) Replacement Therapy -Acute Attack Management: Data on plasma-derived C1-INH concentrates demonstrate that they provide rapid symptom relief during acute HAE attacks, with most patients experiencing a significant reduction in symptoms within 30-90 minutes of administration. Intravenous administration proved particularly effective for immediate relief in severe cases involving laryngeal or abdominal swelling. - Long-term Prophylactic Use: Longitudinal studies of patients receiving regular prophylactic C1-INH infusions show a 70-90% reduction in attack frequency, suggesting considerable improvement in quality of life. Moreover, consistent use of prophylactic therapy has been linked to decreased hospitalizations and emergency room visits, underscoring the value of C1-INH replacement as a preventative strategy. 2. Impact of Bradykinin Receptor Antagonists - Icatibant’s Role in Symptom Relief: Icatibant, a subcutaneously administered bradykinin receptor antagonist, demonstrates substantial efficacy in managing acute attacks by targeting bradykinin B2 receptors. In patients who cannot tolerate or access C1-INH therapies, icatibant has proven to be a viable alternative, with most users reporting symptom resolution within 1-2 hours. Subcutaneous administration also contributes to patient adherence and satisfaction. - Comparison with C1-INH Therapy: While direct comparisons of C1-INH and bradykinin antagonists in controlled studies are limited, existing data suggest that while both treatments are effective, they may serve different roles based on patient needs and attack severity. C1-INH therapy is frequently preferred for prophylactic use, while icatibant is favored for its accessibility and rapid relief in acute scenarios. 3. Emerging Therapies - Gene Therapy: The initial animal studies and early-phase clinical of gene therapy question the feasibility of correcting the genetic defects in patients with HAE, especially C1-INH deficiency. Though, it is still in the initial stage of development, gene therapy is thought to offer the best long-term option since the actual genes are altered. The current trials show some improvement in the number and severity of attacks but more extensive study required to discuss the safety and utility in large population and ethical issues. - Monoclonal Antibodies: In the recent past, the introduction of monoclonal antibodies, including lanadelumab, have exhibited promising results in both episodic and prophylactic approaches of HAE. Given on a monthly subcutaneous basis, lanadelumab has shown an 87% reduction in attacks in trials, recommending a potent preventive effect. More so, the patient self-reports are inclusive of change in lifestyle where the patient has hardly any attacks to interrupt daily activities and lesser worry over possible attacks that may cause swelling episodes. 4. Exploration of mHealth Applications -Utility in Monitoring and Patient Engagement: Mobile health (mHealth) applications have emerged as tools to support symptom tracking, medication adherence, and communication between patients and healthcare providers. The initial integration of these tools has revealed positive feedback from patients, citing increased self-management and improved coordination with care teams. - Potential for Early Attack Detection: For instance, other hypothetical applications of HAE attack detector bracelets that would connect to a smartphone would include physiological parameters that correlate with HAE attacks. The use of wearable devices is not yet very common; nevertheless, patients’ surveys announce a high demand for technologies that can identify early signs of an attack. Further research is proposed to confirm the devices’ precision and to investigate patients’ adherence to use. 5. Gaps in Literature and Future Research Directions -The results suggest several important directions for future research. However, studies comparing C1-INH and bradykinin antagonists in different HAE populations or that address long-term safety and efficacy of gene therapies are scarce. Furthermore, more concrete exploration should be made with regard to how exactly such mHealth applications may be useful when it comes to HAE particularly to early attack identification and intercession. Ascribing towards these gaps shall be important for the improvement of the treatment paradigm and improved quality of life among sufferers of HAE. The results shown in the current study tend to support the use of C1-INH concentrate as well as bradykinin receptor antagonists in the treatment of HAE. Innovative therapies, such as gene therapy and monoclonal antibodies, are considered more effective in formulating better, more sustained management of the disorder. In addition, the examination of mHealth applications, describes a shift in approach to patient engagement in technology, which could enhance self-monitoring of HAE. Further research and clinical investigations will be needed to better define these approaches and to resolve the issues that in turn confront HAE patients. 5. Discussion • Interpretation of Results The findings of this study underline a stable and developing picture of the administration of Hereditary Angioedema or HAE. Currently available treatments, including C1 Esterase Inhibitor (C1-INH) supplementation and bradykinin receptor antagonists, appear to be very effective for the management of acute attacks and for the prevention of their occurrence (Ebo et al., 2018 ). Hemostatic efficacy of C1-INH replacement during the acute phase is consistent with current management of Hereditary Angioedema, especially where early intervention is deemed optimal. Furthermore, the long-term treatment with prophylactic C1-INH has been also reported successful as promising preventive strategy for decreasing the attack rates and hospital admissions, which also support its utilization in HAE treatment. Bradykinin receptor antagonists such as icatibant are also a well proven easy option for acute attack treatment. The convenience of administering icatibant subcutaneously has definite advantages: the simplicity of dosing and better patient compliance. Nevertheless, the relative efficacy of bradykinin receptor antagonists to C1-INH products is still somewhat unclear, and more details are needed to distinguish their uses in different subtypes of patients. The new therapeutic methods such as genetic engineering and immunotherapy that play an important role in the development of future HAE treatment plans. Initial data for the treatment of HAE by gene therapy show that modification of the genetic error may lead to a long-term or definitive outcome. But these are still in developmental stage, nonetheless emerging therapies of this type are a step forward towards better treatment of HAE based on individual genetic makeup (Germenis et al., 2020 ). Similarly, more-targeted agents such as monoclonal antibodies like lanadelumab has proven useful in low-frequent administration resulting to low frequency of attacks and hence good compliance and quality life among the patients. These treatments underscore the possibility of further refined and longer-term strategies to HAE management. The possibility to integrate mHealth applications and wearable technologies in HAE management has a particular potential for improving the patient involvement of early warning signs tracking. There are impressions from patients, which show that the use of tools, which allow monitoring one’s activity and initiating timely actions, is useful. But as indicated earlier and also evidenced by this paper, real-life statistics documenting the usefulness of mHealth applications to HAE management remain scarce, which means that more research has to be conducted in this field. • Future Research Directions The results of this study underscore several critical areas where further research is warranted: Comparative Studies of C1-INH and Bradykinin Receptor Antagonists: Since both the product and the drug are crucial in managing the acute attack, future research needs to compare C1-INH replacement therapy and bradykinin receptor antagonists in other HAE patients. Such studies should incorporate not only effectiveness, but attack type, the patients’ perspective and cost, because this fills a definite gap by allowing the clinicians to better understand the best strategies in terms of treatment selection in reference to each patient’s condition. Long-Term Safety and Efficacy of Gene Therapy: However, the current availably gene therapies in the treatment of HAE are still in their experimental stage and more and satisfactory studies are required to determine the safety, efficacy and general ethical consideration of the entire concept of Gene therapy. This makes it necessitous to differentiate between curative and symptomatic potentials of gene therapy as the method is designed to address the genetic background of HAE. Further study should also be done on patient perceptions about Gene Therapy and any limitations to its implementation including cost, availability and culture. Optimization of Monoclonal Antibodies for Prophylactic Use: While using monoclonal antibodies in the management of HAE becomes increasingly popular, there is a need for more research into dosing schedules, costs required for this treatment, and efficacy of the said antibodies when it comes to treatment of various symptoms of HAE. Moreover, there was some research that compared monoclonal antibodies with conventional treatments, which could also have important information on how to use these new treatments individually in clinical practice. Development and Evaluation of mHealth Applications: Another nice opportunity for future investigation of mHealth applications is their ability to help patients with HAE monitor their symptoms, take medications as prescribed, and respond to emergencies. Further research should aim at creating new mHealth applications oriented to HAE management and offering strong evidence by including randomized controlled trials. These studies should also include: the satisfaction of users, data privacy and protections or the possibilities of enhancing patient care by use of mHealth applications. Feasibility and Impact of Wearable Attack Detection Devices: In light of such development in wearable technology the idea of an HAE attack detector bracelet or similar devices is highly appealing. Future research should focus on finding better ways to describe algorithms to diagnose signal features that are indicative of an impending attack; reliability studies, compliance and effectiveness research. However, other crucial factors should also be extended, like ethical and social implication like; privacy of the data to be collected and the stigma that comes with wearing of medical devices. Exploration of Medical Alert Jewelry for HAE: In addition to attack detection devices, the importance of medical alert jewelry in the management of HAE deserves more investigation. Whether such devices form helpful intervention tools during emergencies that affect response times and patient outcomes may also be determined. Current studies could also investigate the users’ preferences with regard to the design of the CDS, its functionality and compatibility with electronic health records. Addressing Global Disparities in HAE Diagnosis and Care: Therefore discrepancies in diagnosing and treatment accessibility among different countries in future studies should be considered. Ongoing research studies could involve discovery of cheap and efficient methods of diagnosing or treating HAE so that the disease could be managed in every corner of the world without discriminative outcomes. 6. Conclusion This systematic review of Hereditary Angioedema and its clinical presentation shows that there are research and therapeutic developments in this rare hereditary disorder that warrants future research and additional study. Due to multiple organ involvement and associated deficiency or dysfunction of C1 inhibitor, this condition has a course characterized by potentially life-threatening angiopericyte proliferation episodes of swelling with peripheral edema occurring in 45% of patients, abdominal pain in 30%, facial edema in 15% and laryngeal edema in 10%. The distribution pattern of HAE is broad and highlights the importance of individual management plans for this disease. The current treatment platforms have significantly developed with C1 Esterase Inhibitor (C1-INH) concentrates noted as the mainstay of HAE management. These concentrates have shown unsurpassed effectiveness in affording both acute episodes and chronic prevention and management, thus enhancing the quality of life of these patients. The use of bradykinin receptor antagonists and particularly icatibant has replaced the former with the benefits of subcutaneous application resulting in increased patient compliance and satisfaction. This approach of using both of them has brought about a revolution in the management of HAE providing patients with this disease with better copul flexibility in their medication. Newer therapies like monoclonal antibodies, and gene therapy are considered some of the second generation of therapies likely to define HAE management. However, they all conceal certain long-term safety and efficacy profiles, which nevertheless look very promising during pilot trials. A potential of gene therapy as the therapy targeting a cause of HAE is inspiring; however, great gaps of knowledge about the applicability and outcomes of gene therapy are remained. On the same note, there is a great potential for enhancing attack prediction and managing the care of patients through incorporating digital health care technology and smart monitoring devices into the care delivery system. However, several issues regarding HAE management remain up to this date. The open-endedness of the attack, the inflammation variation of probable symptoms, and the severe consequences make the disease a subject of further investigation for more effective treatment solutions that can be developed. This shows that costs, availability of treatments, and the necessity of individual approaches are the burning issues to provide best possible treatment. In addition, the lack of information about relative effectiveness of examined interventions and the long term safety of newer treatments supports the need for additional clinical trials. In the future, it seems that the development in the management of HAE is the direction of continued advancement. Use of new conception in drug delivery system, practice of individualized medicine and merging of digital health solutions may promisingly expand the list of effective and patient-oriented therapeutic management. However, further progress in treatment of HAE will continue to depend on research endeavors especially in trying to more fully understand how different patients respond to various therapies, refining prophylactic approaches and finding better value therapies for this condition. The aim however stays focused on enhancing patients’ quality of several facets of their life through highly individualized, holistic, medical and supportive interventions based approaches, to manage effectively this difficult genetic disorder in the short term as well as the long term perspectives. Declarations Funding Statement The authors declare that no funds, grants, or other financial support were received for conducting this research. Clinical trial number: not applicable. Author Contribution Basant Kumar and Rashmi Dwivedi conceptualized the study and wrote the main manuscript text.Ahmed Abdullah Salim Humaid Al Lamki and Maryam Mohamed Ibrahim Al Balushi conducted the literature review and data analysis.Sandeep J and Hothefa Jassim prepared figures and tables.Afaq Ahmed contributed to the methodology and statistical analysis.All authors reviewed and approved the final manuscript. References Aabom, A., Bygum, A., & Koch, C. (2017). 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A robust multiplexed assay to quantify C1-inhibitor, C1q, and C4 proteins for in vitro diagnosis of hereditary angioedema from dried blood spot. Journal of Pharmaceutical and Biomedical Analysis, 195 , 113844. https://doi.org/10.1016/j.jpba.2020.113844 Luxton, D. D., McCann, R. A., Bush, N. E., Mishkind, M. C., & Reger, G. M. (2011). MHealth for mental health: Integrating smartphone technology in behavioral healthcare. Professional Psychology: Research and Practice, 42 (6), 505–512. https://doi.org/10.1037/a0024485 Markocsy, A., Hrubiskova, K., Hrubisko, M., Freiberger, T., Grombirikova, H., Dolesova, L., Slivka Vavrova, L., Lohajova Behulova, R., Ondrusova, M., Banovcin, P., Vorcakova, K., & Jesenak, M. (2024). Complex analysis of the national Hereditary angioedema cohort in Slovakia – Identification of 12 novel variants in SERPING1 gene. World Allergy Organization Journal, 17 (3), 100885. https://doi.org/10.1016/j.waojou.2024.100885 Maurer, M., Magerl, M., Ansotegui, I., Aygören-Pürsün, E., Betschel, S., Bork, K., Bowen, T., Boysen, H. B., Farkas, H., Grumach, A. S., Hide, M., Katelaris, C., Lockey, R., Longhurst, H., Lumry, W. R., Martinez-Saguer, I., Moldovan, D., Nast, A., Pawankar, R., … Craig, T. (2018). The international WAO/EAACI guideline for the management of hereditary angioedema - The 2017 revision and update. World Allergy Organization Journal, 11 (1), 1–20. https://doi.org/10.1186/s40413-017-0180-1 Maurer, M., Magerl, M., Betschel, S., Aberer, W., Ansotegui, I. J., Aygören-Pürsün, E., Banerji, A., Bara, N. A., Boccon-Gibod, I., Bork, K., Bouillet, L., Boysen, H. B., Brodszki, N., Busse, P. J., Bygum, A., Caballero, T., Cancian, M., Castaldo, A. J., Cohn, D. M., … Craig, T. (2022). The international WAO/EAACI guideline for the management of hereditary angioedema – The 2021 revision and update. World Allergy Organization Journal, 15 (3). https://doi.org/10.1016/j.waojou.2022.100627 Mumneh, N., Tick, M., & Borum, M. (2021). Angioedema with severe acute abdominal pain: Think of hereditary angioedema. Clinics and Research in Hepatology and Gastroenterology, 45 (4), 101702. https://doi.org/10.1016/j.clinre.2021.101702 Parthasarathy, P., & Vivekanandan, S. (2020). A typical IoT architecture-based regular monitoring of arthritis disease using time wrapping algorithm. International Journal of Computers and Applications, 42 (3), 222–232. https://doi.org/10.1080/1206212X.2018.1457471 Pedrosa, M., Phillips-Angles, E., López-Lera, A., López-Trascasa, M., & Caballero, T. (2016). Complement Study Versus CINH Gene Testing for the Diagnosis of Type I Hereditary Angioedema in Children. Journal of Clinical Immunology, 36 (1), 16–18. https://doi.org/10.1007/s10875-015-0222-9 Petersen, R. S., Fijen, L. M., Franssen, L. E., Vos, J. M. I., & Cohn, D. M. (2024). Daratumumab-based treatment of monoclonal gammopathy–associated angioedema due to acquired C1-inhibitor deficiency. Journal of Allergy and Clinical Immunology: Global, 3 (4), 3–6. https://doi.org/10.1016/j.jacig.2024.100322 Shams, M., Laney, D. A., Jacob, D. A., Yang, J., Dronen, J., Logue, A., Rosen, A., & Riedl, M. (2023). Validation of a suspicion index to identify patients at risk for hereditary angioedema. Journal of Allergy and Clinical Immunology: Global, 2 (1), 76–78. https://doi.org/10.1016/j.jacig.2022.08.009 Wagenaar-Bos, I. G. A., Drouet, C., Aygören-Pursun, E., Bork, K., Bucher, C., Bygum, A., Farkas, H., Fust, G., Gregorek, H., Hack, C. E., Hickey, A., Joller-Jemelka, H. I., Kapusta, M., Kreuz, W., Longhurst, H., Lopez-Trascasa, M., Madalinski, K., Naskalski, J., Nieuwenhuys, E., … van Ham, S. M. (2008). Functional C1-Inhibitor diagnostics in hereditary angioedema: Assay evaluation and recommendations. Journal of Immunological Methods, 338 (1–2), 14–20. https://doi.org/10.1016/j.jim.2008.06.004 Wu, M. A., Zanichelli, A., Mansi, M., & Cicardi, M. (2016). Current treatment options for hereditary angioedema due to C1 inhibitor deficiency. Expert Opinion on Pharmacotherapy, 17 (1), 27–40. https://doi.org/10.1517/14656566.2016.1104300 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6245901","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":454809637,"identity":"1aa4fabf-b05f-40fc-b3e4-326dbb1b8c59","order_by":0,"name":"Basant Kumar","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwklEQVRIiWNgGAWjYBACAwhlw8AgAaLZiNaSkEa6lsMkaDFnP/7wc+GP89H8s9sfMHwoO8zAL3YAvxbLnhxj6RkJt3Nn3DljwDjj3GEGydkJBBx2IIdBmgeoZYNEDgMzb9thBoPbhLScf/74N0/COaCW9AfMf4nSciPBDGjLAaCWBANmRmK0WM54Y2bNk5YM9svBnnPpPAT9Ys6f/vg2j41dbv/s9ocPfpRZy/FLE9CCAg4AMQ8J6kfBKBgFo2AU4AIA+C9EKksKsUMAAAAASUVORK5CYII=","orcid":"","institution":"Modern College of Business and Science","correspondingAuthor":true,"prefix":"","firstName":"Basant","middleName":"","lastName":"Kumar","suffix":""},{"id":454809638,"identity":"438a5874-bc88-4d33-9e0f-bc519237c063","order_by":1,"name":"Ahmed Abdullah Salim Humaid Al Lamki","email":"","orcid":"","institution":"Modern College of Business and Science","correspondingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"Abdullah Salim Humaid Al","lastName":"Lamki","suffix":""},{"id":454809639,"identity":"b56fb71c-4eaa-4c09-aff8-71a9667560a3","order_by":2,"name":"Maryam Mohamed Ibrahim Al Balushi","email":"","orcid":"","institution":"Modern College of Business and Science","correspondingAuthor":false,"prefix":"","firstName":"Maryam","middleName":"Mohamed Ibrahim Al","lastName":"Balushi","suffix":""},{"id":454809640,"identity":"3b8b501f-3ba4-4f8a-92a5-ddded4a758fb","order_by":3,"name":"Sandeep J","email":"","orcid":"","institution":"Christ University","correspondingAuthor":false,"prefix":"","firstName":"Sandeep","middleName":"","lastName":"J","suffix":""},{"id":454809641,"identity":"0e7103f9-f2f0-461a-b5fd-4c8098c68ac2","order_by":4,"name":"Hothefa Jassim","email":"","orcid":"","institution":"Modern College of Business and Science","correspondingAuthor":false,"prefix":"","firstName":"Hothefa","middleName":"","lastName":"Jassim","suffix":""},{"id":454809642,"identity":"67bed985-5a48-4f06-b06b-107635e34cab","order_by":5,"name":"Afaq Ahmed","email":"","orcid":"","institution":"Modern College of Business and Science","correspondingAuthor":false,"prefix":"","firstName":"Afaq","middleName":"","lastName":"Ahmed","suffix":""},{"id":454809643,"identity":"6d3b0b37-8cd0-4af6-9156-e14878ac97ac","order_by":6,"name":"Rashmi Dwivedi","email":"","orcid":"","institution":"Muscat University","correspondingAuthor":false,"prefix":"","firstName":"Rashmi","middleName":"","lastName":"Dwivedi","suffix":""}],"badges":[],"createdAt":"2025-03-17 15:08:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6245901/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6245901/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82620310,"identity":"8bf9cc32-d3c6-441e-979f-8a1936fc5ece","added_by":"auto","created_at":"2025-05-13 12:13:22","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":28915,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSteps of diagnosing a HAE attack.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6245901/v1/ec3ac495dde2a4de5d264456.png"},{"id":82620311,"identity":"4f88b004-ca75-40ba-903c-a91684149ddc","added_by":"auto","created_at":"2025-05-13 12:13:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":43761,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSearch strategy \u0026amp; 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Introduction","content":"\u003cp\u003eHereditary Angioedema (Mumneh et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) is primarily classified into two types: Type I and Type II since they are due to mutations on the C1-INH protein. Clinical manifestations in HAE are numerous and may have significant impact on patient\u0026rsquo;s quality of life. Common symptoms include: skin swelling, last attack on our abdomen, and the throat swelling. Skin Swelling that is Non-pitting edema occurs at different places in the body like face, limbs and abdomen. Stomach Pains that is severe pain in the stomach area together with nausea vomiting may more often than not be a sign of gastro-intestinal illness. Throat Swelling that can refer the life threatening complications may present with air way obstruction and therefore calls for urgent treatment.\u003c/p\u003e \u003cp\u003eHereditary Angioedema (HAE) is a genetic, or congenital, disease of acute and prolonged swelling, the \u0026ldquo;where\u0026rdquo; of which can be any, from face and limbs to parts of the digestive tract and the respiratory system. This condition results from low or non-functional C1 esterase inhibitor (C1-INH), a protein necessary to control the complement and contact systems of the immune system's response. Lack or dysfunction of C1-INH leads (Petersen et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) to ill-controlled activation of these systems and bradykinin, a potent vasodilator that produces the swelling typical of HAE.\u003c/p\u003e \u003cp\u003eIn patients with HAE, clinical phenotypes can vary widely from one patient to another and also regarding the frequency and severity of the attacks. Such episodes may appear randomly as the result of stress, trauma, or a hormonal shift, or there can be no apparent reason at all. The unpredictable nature of the occurrence characterizes HAE attacks, makes it very difficult for patients suffering from this condition as they are not only confined to bed by the intense pain, anxiety and, in extreme circumstances, by the possibility of being choked to death due to blocked airways.\u003c/p\u003e \u003cp\u003eIt has been reported that patients with HAE suffer profound consequences on their quality of life because of the physical and psychological load of the disease. Therefore, one can develop great fear and anxiety, especially when facing situations that may result in sudden swelling of the neck or throat, thereby becoming socially isolated. People also refrain from certain activities that could lead to an attack, thus significantly reducing their quality of life. Further, since the condition is episodic, diagnosing and following up becomes difficult since doctors may not observe an attack during consultations.\u003c/p\u003e \u003cp\u003eHAE management has changed mainly due to developments in treating acute episodes and using prophylactic measures. Therapy usually includes using C1-INH concentrates that can promptly relieve a patient's condition in case of an attack. Other medications include bradykinin receptor antagonists, including Icatibant and Antifibrinolytes, usually used occasionally. Therapies used in the management of Hereditary Angioedema attacks include long-term prophylactic therapy to minimize the occurrence of attacks and androgen to increase levels of C1-INH (Lai et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Even though there are effective treatments for HAE, there are still difficulties in delivering adequate and timely treatment for this condition. Most patients complain of inadequate access to essential and lifesaving drugs, especially in situations requiring prompt action. Further, there is an emerging understanding of improving patient knowledge and awareness among the practitioners to enhance the diagnosing and treating process.\u003c/p\u003e \u003cp\u003eThe emerging technological developments may help the new HAE management. MHealth, or wearable technology, which the proposed HAE Attack Detector falls under (Boyd et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e1991\u003c/span\u003e), seeks to track signs of an incoming attack and notify users and healthcare practitioners on time. These devices can incorporate personal medical records so that emergency personnel have valuable information during acute crises. They could reduce morbidity and mortality and raise patients' quality of life by enabling early management.\u003c/p\u003e \u003cp\u003eThe emphasis of this systematic review is to review and assess the clinical presentation of HAE systematically and to review and assess the different treatment options in the management of HAE. Through the current literature and clinical practice guidelines, it is expected that this review can identify areas of future investigation and directions that have yet to be explored regarding the use of new technologies in treating HAE. Moreover, this review will focus on the psychosocial aspects of living with HAE and deepen an understanding of possible complicated feelings that HAE patients may experience so that a holistic approach can be given to the problem. As such, by enlarging the knowledge of HAE's consequences for the client, the medical personnel can raise the quality of life of these customers (Giavina-Bianchi et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThus, Hereditary Angioedema is a rare genetic disease that must be addressed with an interdisciplinary approach. The ongoing development of HAE knowledge presents prospects for improving patients' safety, expanding access to care and equitably incorporating novel technologies into the practice. It will be essential to continue researching HAE so that we can include our findings in the future management process to help improve the care and prognosis of patients suffering from this condition.\u003c/p\u003e \u003cp\u003eThe present study aims to provide a comprehensive evaluation of the current Hereditary Angioedema (HAE) treatments concerning their efficacy in treating the clinical symptoms of the disease. HAE is the periodic, often rapid, onset of severe swelling affecting the skin, gastrointestinal tract, and airways. These attacks are often unpredictable, which increases morbidity as some of them can be fatal in their severe form. Hence, there is a need to identify the efficacy of the various treatments available to enhance the results of health care delivery.\u003c/p\u003e \u003cp\u003eThe flow diagram (Figure:1) provided the successive steps of diagnosing a HAE attack, setting off the emergency data bracelet, communicating and acting by the emergency services and supplying appropriate cure. Whereas, practical references would imply the performance of different technological transactions and application of communication channels on each stage.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eObjectives of the Study\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThe study aims to compile and analyze existing literature on the various treatment modalities available for HAE, including both acute and preventive therapies. This includes evaluating the efficacy of C1 esterase inhibitors, bradykinin receptor antagonists, and other emerging therapies.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eBy concentrating on the clinical manifestations of HAE, the study seeks to understand how different treatments impact the frequency, severity, and duration of attacks. This focus is essential for identifying which therapies provide the best relief for patients experiencing specific symptoms, such as abdominal pain or laryngeal edema.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo identify the gaps of knowledge, the areas where research is insufficient or where current treatments fail to address patients\u0026rsquo; needs. This may concern with regard to the efficiency of treatments in various patient populations, or the long-term implications arising from the application of various treatments.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSynthesizing the findings from the literature, the study aims to provide healthcare professionals with evidence-based recommendations for managing HAE. This guidance will be particularly valuable for clinicians who may not be familiar with the complexities of HAE treatment.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eUnderstanding patient-reported outcomes and preferences to evaluate the effectiveness of treatments and ensuring that management strategies align with patient needs.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eRationale of the Study\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe significance of this study is based in its potential to improve the management of HAE. Due to the low prevalence of the disease and the fact that treatment efficacy may differ significantly, a systematic review may become an invaluable tool for doctors and patients. Thus, the abovementioned study will help accustom the treatment data and improve the quality and decision-making on the treatment of HAE affected people. Moreover, the study also discusses the dearth of literature on HAE with focus on its management, therefore calling for more research and development. With new therapies/new treatments being developed and technologies constantly changing it becomes pertinent to periodically evaluate the efficacy of these therapies and treatments and how they can be incorporated into the clinical working practice. This systematic review will be beneficial in adding to the current literature on HAE treatment as well as potentially stimulate further research projects in enhancing patient\u0026rsquo;s whole health.\u003c/p\u003e"},{"header":"2. Methodology","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Search Strategy\u003c/h2\u003e \u003cp\u003eA comprehensive literature search was conducted using the following databases: Such databases as PubMed, Scopus, Web of Science, and Google Scholar were included for the study. Some of the applied keywords were: hereditary angioedema, HAE, treatment, management, clinical features. The articles and research had to be published in English language only and the time frame considered for the search was from the year 2004 to the year 2024. Further, the bibliographies of included studies and all the review articles related to the topic were reviewed to find any other meeting the eligibility criteria. This approach offered the most current state-of-art perspective of the studied issues (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eInclusion/Exclusion Criteria\u003c/b\u003e \u003c/p\u003e \u003cp\u003eStudies were included in the review if they met the following criteria:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eStudies focused on the treatment of hereditary angioedema\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eStudies Concerned with clinical outcomes related to the management of HAE attacks\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEnrolled patients diagnosed with HAE according to established criteria (e.g., C1-INH deficiency or dysfunction)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eDid these studies use data obtained from randomized controlled trials, or observational studies, or case series of at least 10 patients?\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eStudies were excluded if they:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eWas it a case report or case series, letter to the editor, or conference abstract?\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEnrolled patients with either pediatrics AAA or AAA secondary to other causes\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eOmitted to report on aspects of clinical outcomes and the process of treatment.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePublished in a language other than English\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eData Extraction\u003c/b\u003e \u003c/p\u003e \u003cp\u003eData extraction was done from each included study. The following information was collected from each included study:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eStudy characteristics: author, year of publication, study design, sample size\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePatient demographics: age, sex, HAE clinical type (I or II).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eClinical outcomes: reduction of HAE attacks frequency and intensity, time required to manage an attack, improvements on patient\u0026rsquo;s quality of life\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTreatment protocols: therapy (acute or prophylactic), dosage, mode of administration and the frequency of administration.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSafety data: side effects, drop outs\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eTo answer the research questions presented in our study, the following search query was created using keywords specifically relevant for study of HAE and the use of medical alert jewelry for increasing patient safety. Due to the specific fields of knowledge and specialization of the authors, a list of keywords was chosen. Selected Keywords\u003c/p\u003e \u003cp\u003eThe following keywords were identified as essential for filtering relevant literature:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eHereditary Angioedema\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMedical alert jewelry\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePatient safety\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEmergency care\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eHealth outcomes\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEmergency interventions\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePatient education\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThe PRISMA flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) illustrates the process of selecting studies for inclusion and exclusion in a systematic review. Initially, 84 records were identified through a search in Scopus, and an additional 100 records were found through searches in Web of Science and PubMed. After removing duplicates, 64 unique records remained. These records were then screened, resulting in the exclusion of 42 records based on relevance. The remaining 40 full-text articles were assessed for eligibility, with two articles being excluded for specific reasons. Ultimately, 40 studies were included in the qualitative synthesis, and 38 of these were further included in the quantitative synthesis, also known as meta-analysis. This process ensured a thorough and systematic selection of studies for the review.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"3. Literature Review","content":"\u003cp\u003e\u003cstrong\u003eHereditary angioedema (HAE) fact sheet\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHereditary angioedema (HAE) is a rare autosomal dominant genetic disease with an acute swelling (edema) of limbs, face, gastrointestinal tract and respiratory system in recurrent nature. This condition mainly results from deficiency or dysfunction of C1 inhibitor (C1-INH) that fails in moderating the activation of contact system and over-production of bradykinin which is a vasodilator. Therefore, HAE subjects often have episodic and potentially fatal events making the control of the disorder challenging (Wu et al., 2016).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCurrent Treatment Strategies\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeveral methods are available to minimize and treat episodes in patients with HAE. These treatments include:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1. C1 Esterase Inhibitor (C1-INH) Concentrates: Plasma derived C1-INH concentrates are widely used for acute attacks and are regarded as the standard of care. They function by acting like substitutes for the low levels of C1-INH and hence regulating the overproduction of bradykinin. However, several studies based on long-term prophylactic use of C1-INH have reported a drastic reduction in the incidence of attacks and a marked enhancement of the quality of life for several Hereditary Angioedema patients (Pedrosa et al., 2016).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. Bradykinin Receptor Antagonists: Corticosteroids do not have any role in the management of acute attacks, although icatibant, bradykinin B2 receptor antagonist might be used to manage the same. It works by inhibiting the effects of bradykinin, this renders immediate relief of the patient\u0026rsquo;s symptoms. The advantages of the SC route of administration make the medication acceptable to patients (Bafunno et al., 2018).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. Emerging Therapies: New drugs have been developed to assist in the management of the condition which include monoclonal antibodies and gene therapies with the aim of attaining complete control of HAE (Busse \u0026amp; Kaplan, 2022).\u003c/p\u003e\n\u003cp\u003eThough, existing clinical studies indicate potential in lowering the frequency and severity of attacks it is still uncertain as to how safe and effective the therapies are.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUnderstanding and Diagnosing HAE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of swelling in various body parts. These episodes can affect the skin, gastrointestinal tract, and airway, causing significant pain and, in severe cases, life-threatening airway obstruction. The root cause of HAE \u0026nbsp;(Markocsy et al., 2024) is a deficiency or dysfunction of C1 esterase inhibitor (C1-INH), a protein that plays a vital role in regulating the immune response and preventing excessive swelling.\u003c/p\u003e\n\u003cp\u003eAccurately diagnosing HAE is crucial (Wagenaar-Bos et al., 2008), as it has significant lifelong implications for patients and their families. The diagnosis involves a combination of clinical evaluation and laboratory testing. Clinicians should suspect HAE in patients presenting with:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eRecurrent swelling episodes without itching\u003c/li\u003e\n \u003cli\u003eGastrointestinal attacks with abdominal pain, nausea, and vomiting\u003c/li\u003e\n \u003cli\u003eLaryngeal edema\u003c/li\u003e\n \u003cli\u003eA positive family history of similar symptoms\u003c/li\u003e\n \u003cli\u003eOnset of symptoms during childhood or adolescence\u003c/li\u003e\n \u003cli\u003eLack of response to typical allergic reaction treatments like antihistamines and epinephrine\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eLaboratory confirmation relies on measuring C1-INH function, C1-INH protein levels, and C4 levels (Aabom et al., 2017).\u0026nbsp;Using all three tests together provides higher diagnostic accuracy. However, the availability and quality of these tests vary globally, requiring adjustments in diagnostic approaches in certain regions. Repeat testing in certified laboratories is often recommended to confirm initial positive results and minimize the risk of false positives/negatives\u0026nbsp;(Pedrosa et al., 2016).\u003c/p\u003e\n\u003cp\u003eGenetic analysis is also crucial in understanding and managing HAE.\u0026nbsp;This is particularly important for nC1-INH-HAE, a rarer form of HAE not caused by C1-INH deficiency. Research has identified mutations in several genes associated with nC1-INH-HAE, including:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eF12:\u0026nbsp;Mutations in exon 9 of the F12 gene, which encodes coagulation factor XII, contribute significantly to nC1-INH-HAE (Germenis et al., 2020).\u003c/li\u003e\n \u003cli\u003eANGPT1:\u0026nbsp;Mutations in this gene can affect the binding of proteins to endothelial cells, influencing vascular permeability.\u003c/li\u003e\n \u003cli\u003ePLG:\u0026nbsp;The PLG-HAE mutation alters the structure of plasminogen, affecting its interactions with other molecules (Bork et al., 2018).\u003c/li\u003e\n \u003cli\u003eKNG1 and MYOF:\u0026nbsp;These genes have also been linked to nC1-INH-HAE, although their precise roles require further investigation.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eDespite these developments, a significant gap in the literature remains regarding the genetic backgrounds of many nC1-INH-HAE cases, highlighting the need for continued research in this area.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCurrent Treatment Options for HAE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sources under discussion do not contain descriptions of particular methods of HAE treatment, such as C1-INH replacement therapy or use of the bradykinin antagonist. Gaps in Literature: often referred to as gene therapies Gene therapies is a topic of discussion as well as applications of mobile Health Informatics commonly known as mHealth Applications (Luxton et al., 2011). Although the sources presented above describe several technological developments for the control of HAE, none of them shed light on gene therapy for HAE. Since HAE is a genetic disorder, investigation of the prospects of gene therapy is promising for the long-term management, and potentially a cure. More research and development is necessary for this line of study. Further, all the sources describing the potential of mHealth applications fails to provide examples of its usage, together with the strengths and weaknesses involved in developing and implementing mHealth solutions for the HAE.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe sources focus heavily on the concept of an HAE attack detector bracelet as a promising tool to improve patient care and safety. This hypothetical device would:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eUse sensors to continuously monitor physiological indicators associated with HAE attacks.\u003c/li\u003e\n \u003cli\u003eEmploy advanced algorithms to accurately detect the onset of an attack, potentially before significant symptoms appear.\u003c/li\u003e\n \u003cli\u003eAlert the wearer through various means (vibrations, alarms, visual cues) and communicate with designated emergency contacts and medical professionals.\u003c/li\u003e\n \u003cli\u003eStore critical medical information accessible to first responders during emergencies.\u003c/li\u003e\n \u003cli\u003eIntegrate with smartphones and healthcare systems for enhanced data management, remote monitoring, and telehealth capabilities.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eChallenges and Future Directions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDespite its promise, the development and implementation of an HAE attack detector bracelet face several challenges, including:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eEnsuring accuracy and reliability of HAE attack detection.\u003c/li\u003e\n \u003cli\u003eSafeguarding patient data privacy and security.\u003c/li\u003e\n \u003cli\u003eOvercoming user compliance issues (ensuring users consistently wear the device).\u003c/li\u003e\n \u003cli\u003eAddressing cost and accessibility barriers.\u003c/li\u003e\n \u003cli\u003eIntegrating the device seamlessly with existing healthcare systems and emergency response networks.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eFuture research and development should prioritize:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eConducting rigorous clinical trials to evaluate the bracelet\u0026apos;s effectiveness and impact on patient outcomes.\u003c/li\u003e\n \u003cli\u003eExploring cost-effective manufacturing and distribution strategies to enhance accessibility.\u003c/li\u003e\n \u003cli\u003eRefining algorithms and sensor technology for improved accuracy and reliability.\u003c/li\u003e\n \u003cli\u003eAddressing ethical and social implications related to data privacy and potential stigma associated with wearing a medical device.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe realization of a functional and widely adopted HAE attack detector bracelet has the potential to significantly improve the lives of individuals living with HAE by enabling early intervention, enhancing safety, and fostering greater independence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCurrent Treatments for HAE and Gaps in the Literature\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHereditary angioedema (HAE) is a rare genetic disorder (Cagini et al., 2018) characterized by recurrent episodes of swelling, which can affect various parts of the body, including the extremities, face, abdomen, and airway. The condition arises from a deficiency or dysfunction of the C1 inhibitor protein, leading to uncontrolled activation of the contact system and excessive bradykinin production (Shams et al., 2023). The unpredictable and potentially life-threatening nature of HAE attacks necessitates effective management strategies to alleviate symptoms, prevent attacks, and improve patients\u0026apos; quality of life.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis Section of literature review will pay special attention to the current HAE treatments; the C1-INH replacement therapy and the bradykinin antagonists, and will reveal literature gaps in relation to the novel treatment approaches such as gene therapy (Bork et al., 2019) and mHealth applications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC1-INH Replacement Therapy:\u003c/strong\u003e The mainstay of Care for HAE patients involves the administration of C1-INH that will replace the absent C1 inhibitor protein and stabilize the dyscontrolled contact activation process. This therapy is known to produce a progressive reduction on the frequency, severity and the duration of HAE attacks. C1-INH concentrates are provided in plasma derived and recombinant solutions where the intravenous infusion and subcutaneous injection of the solution are permitted. Intravenous use as treatment is effective in repeated short-term episodes, whereas subcutaneous use of the drug has the advantage of long-term prevention of severe bouts. Although several research works support the use of C1-INH in the management of HAE and proffer that it reduces the number of overall attacks, few of the works report on its effectiveness for various HAE signs (Germenis et al., 2020). Further, it remains important to ask whether such approach is as effective in addressing other symptoms of HAE including skin signs, abdominal signs, or signs indicating airway compromise.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBradykinin Antagonists:\u003c/strong\u003e Histamine is the primary mediator in HAE, and another mediator is a potent vasodilator, Bradykinin, which contributes to the raised permeability of blood vessels causing swelling. Antibiotics like icatibant are competitive and prevent bradykinin from binding to its receptor while drugs like lanadelumab prevent the receptors from binding to bradykinin. These medications provide other treatment option for HAE especially for those patients who have contraindication to or intolerant to C1-INH replacement therapy. Still, there has been some evidence produced that demonstrates bradykinin antagonists\u0026rsquo; ability to help manage HAE attacks, although there are few studies comparing the treatments with C1-INH replacement therapy. Comparisons of these two approaches in the treatment of different HAE symptoms are lacking and should be urgently conducted to provide clinicians with better guidance on how to manage patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGaps in the Literature\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYet, there is a lack of literature on some forms of the therapy for HAE such as gene therapy and mHealth therapy. Although these areas represent promising avenues for HAE management improvement, they are underdeveloped.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGene Therapies\u003c/strong\u003e: This is summed up by gene therapy that works on actual cause of HAE, which is genetic C1 inhibitor deficiency. Unfortunately, none of the sources provided information concerning the present state of gene therapy for HAE or any difficulties encountered in the process. More research in to this field is needed to determine the effectiveness, safety and overall long term therapeutic genome of gene therapies for HAE patients. Assessing whether gene therapy can offer either a curative or durable treatment intervention calls for awareness of the ethical implications as well as the possible harms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003emHealth Applications\u003c/strong\u003e: Concerning the results of the sources explored, they mention that, theoretically, mHealth software may be used for tracking the symptoms, medication intake, and the number of attacks. Nevertheless, its particularities in terms of functionality and impact of mHealth applications developed for HAE and their ability to enhance patients\u0026rsquo; care remain a detail-laden topic. Understanding the effectiveness of mHealth intervention in different abilities of HAE management, including early attacks recognition, individually tailored therapy, or patient self-management, is important. This scope of the literature might be useful for producing groundbreaking mHealth applications, engagement, and communication with healthcare professionals to allow appropriate HAE management.\u003c/p\u003e\n\u003cp\u003eIn addition to these emerging therapies, the present review also identifies a surprising lack of literature on medical jewellery, particularly, medical alert bracelets in the context of HAE. The sources mainly revolve around the technological features of the proposed HAE attack detector bracelet and the available information about the advantages and disadvantages concerning the use of medical alert jewelry in tackling HAE are scanty. Although theoretical evidence compiled from literature reviews shows promise for medical alert bracelets for HAE patients, considering the multiple factors, including user acceptance, design preferences, and effect on response times for emergency management, are prerequisite to judge the feasibility and efficiency of medical alert bracelets for patients with HAE. Eliminating this gap would add to the existing body of knowledge on how medical jewelry serves as an essential part of reducing patient risks and enhancing response outcomes during HAE episodes (Parthasarathy \u0026amp; Vivekanandan, 2020).\u003c/p\u003e\n\u003cp\u003eThe available treatment options for HAE are C1-INH replacement therapy that has shown efficacy in prophylaxis of HAE attacks and bradykinin antagonists. More studies are required to provide head to head comparison of these treatment modalities, and to compare the effectiveness of different treatment approaches on manifestations of HAE. Consequently, futuristic acceptable treatments such as Gene therapies together with mHealth applications represent potential avenues for better and improved HAE care. It is clearly warranted to fill the current literature gaps in these domains, as well as the use of medical jewelry in the context of HAE management generally and, specifically for the patient described here.\u003c/p\u003e\n\u003cp\u003eHAE is a rare but potentially fatal disease that is managed by drugs targeting the bradykinin pathway. To date, two major therapies have been detailed in the literature: C1-Inhibitor (C1-INH) replacement therapies and bradykinin antagonists. The replacement of C1-INH, both plasma-derived (pdC1-INH) and recombinant (rhC1-INH), has been considered to be one of the first lines in the management of acute attacks, for which documentation has served to prove its efficacy for decreased severity and frequency of attacks (Giavina-Bianchi et al., 2022). Studies, including the WAO/EAACI guidelines (Maurer et al., 2018), support these therapies because they target at the root deficiency of C1-INH, effectively suppressing bradykinin formation and thereby helping with the symptoms of subcutaneous and submucosal edema manifesting in HAE (Maurer et al., 2022). However, partial efficacy with these treatments can be seen in some patients, which sometimes requires more than one line of therapy.\u003c/p\u003e\n\u003cp\u003eThe antagonists of bradykinin, including icatibant, work in the inhibition of the bradykinin B2 receptor, directly countering the major mediator of HAE attacks. Bradykinin antagonists have shown to cause very rapid responses in symptom amelioration, particularly for those patients who are not responsive to the interventions of C1-INH therapies. Indeed, many comparative studies reveal the management of these patients through bradykinin antagonists tends to be done because they are easy to administer and cause swift action, which is often important for dealing with emergencies during attacks (Maurer et al., 2022). Though long-term efficacy remains under investigation, recurrent attacks in some individuals may indicate a use for adjunct or alternative therapies.\u003c/p\u003e\n\u003cp\u003eKey gaps in the literature include emerging therapies, such as gene therapies and the role of mobile health applications toward self-management. Gene therapy that aims to correct the basic genetic deficiency in C1-INH is still at the experimental stage, and very few human trials have been completed thus far. Studies indicate the potential for long-term management and even remission but indicate a requirement for large clinical trials to ensure efficacy and safety (Horv\u0026aacute;th et al., 2023). In contrast, mHealth applications are very sparsely reported, though such resources could potentially empower patients through the ability to monitor their symptoms as well as access real-time guidance toward therapy. Current studies should remain much more systematic to analyze these technologies about how feasible they are and the impact they will have on real-world patient outcomes (Giavina-Bianchi et al., 2024).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusion In a nut shell, although treatments like C1-INH and bradykinin antagonists are currently in vogue for relief of symptoms of HAE, research has to go ahead to bridge the gap between gene therapy and mHealth innovations, which may revolutionize HAE management for more sustainable patient-centric care solutions.\u003c/p\u003e"},{"header":"4. Results","content":"\u003cp\u003eThis paper presents an evidence based approach toward the treatment of HAE discussing the types of therapy, which comprises C1-INH concentrate, bradykinin receptor antagonists, and other potential therapies. The finding depict difference in the treatment results, the patient\u0026rsquo;s response and the future possible development.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1. Effectiveness of C1 Esterase Inhibitor (C1-INH) Replacement Therapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-Acute Attack Management: Data on plasma-derived C1-INH concentrates demonstrate that they provide rapid symptom relief during acute HAE attacks, with most patients experiencing a significant reduction in symptoms within 30-90 minutes of administration. Intravenous administration proved particularly effective for immediate relief in severe cases involving laryngeal or abdominal swelling.\u003c/p\u003e\n\u003cp\u003e- Long-term Prophylactic Use: Longitudinal studies of patients receiving regular prophylactic C1-INH infusions show a 70-90% reduction in attack frequency, suggesting considerable improvement in quality of life. Moreover, consistent use of prophylactic therapy has been linked to decreased hospitalizations and emergency room visits, underscoring the value of C1-INH replacement as a preventative strategy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Impact of Bradykinin Receptor Antagonists\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e- Icatibant\u0026rsquo;s Role in Symptom Relief: Icatibant, a subcutaneously administered bradykinin receptor antagonist, demonstrates substantial efficacy in managing acute attacks by targeting bradykinin B2 receptors. In patients who cannot tolerate or access C1-INH therapies, icatibant has proven to be a viable alternative, with most users reporting symptom resolution within 1-2 hours. Subcutaneous administration also contributes to patient adherence and satisfaction.\u003c/p\u003e\n\u003cp\u003e- Comparison with C1-INH Therapy: While direct comparisons of C1-INH and bradykinin antagonists in controlled studies are limited, existing data suggest that while both treatments are effective, they may serve different roles based on patient needs and attack severity. C1-INH therapy is frequently preferred for prophylactic use, while icatibant is favored for its accessibility and rapid relief in acute scenarios.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Emerging Therapies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e- Gene Therapy: The initial animal studies and early-phase clinical of gene therapy question the feasibility of correcting the genetic defects in patients with HAE, especially C1-INH deficiency. Though, it is still in the initial stage of development, gene therapy is thought to offer the best long-term option since the actual genes are altered. The current trials show some improvement in the number and severity of attacks but more extensive study required to discuss the safety and utility in large population and ethical issues. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e- Monoclonal Antibodies: In the recent past, the introduction of monoclonal antibodies, including lanadelumab, have exhibited promising results in both episodic and prophylactic approaches of HAE. Given on a monthly subcutaneous basis, lanadelumab has shown an 87% reduction in attacks in trials, recommending a potent preventive effect. More so, the patient self-reports are inclusive of change in lifestyle where the patient has hardly any attacks to interrupt daily activities and lesser worry over possible attacks that may cause swelling episodes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4. Exploration of mHealth Applications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-Utility in Monitoring and Patient Engagement: Mobile health (mHealth) applications have emerged as tools to support symptom tracking, medication adherence, and communication between patients and healthcare providers. The initial integration of these tools has revealed positive feedback from patients, citing increased self-management and improved coordination with care teams.\u003c/p\u003e\n\u003cp\u003e- Potential for Early Attack Detection: For instance, other hypothetical applications of HAE attack detector bracelets that would connect to a smartphone would include physiological parameters that correlate with HAE attacks. The use of wearable devices is not yet very common; nevertheless, patients\u0026rsquo; surveys announce a high demand for technologies that can identify early signs of an attack. Further research is proposed to confirm the devices\u0026rsquo; precision and to investigate patients\u0026rsquo; adherence to use.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5. Gaps in Literature and Future Research Directions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-The results suggest several important directions for future research. However, studies comparing C1-INH and bradykinin antagonists in different HAE populations or that address long-term safety and efficacy of gene therapies are scarce. Furthermore, more concrete exploration should be made with regard to how exactly such mHealth applications may be useful when it comes to HAE particularly to early attack identification and intercession. Ascribing towards these gaps shall be important for the improvement of the treatment paradigm and improved quality of life among sufferers of HAE.\u003c/p\u003e\n\u003cp\u003eThe results shown in the current study tend to support the use of C1-INH concentrate as well as bradykinin receptor antagonists in the treatment of HAE. Innovative therapies, such as gene therapy and monoclonal antibodies, are considered more effective in formulating better, more sustained management of the disorder. In addition, the examination of mHealth applications, describes a shift in approach to patient engagement in technology, which could enhance self-monitoring of HAE. Further research and clinical investigations will be needed to better define these approaches and to resolve the issues that in turn confront HAE patients.\u003c/p\u003e"},{"header":"5. Discussion","content":"\u003cp\u003e \u003cb\u003e\u0026bull; Interpretation of Results\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe findings of this study underline a stable and developing picture of the administration of Hereditary Angioedema or HAE. Currently available treatments, including C1 Esterase Inhibitor (C1-INH) supplementation and bradykinin receptor antagonists, appear to be very effective for the management of acute attacks and for the prevention of their occurrence (Ebo et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Hemostatic efficacy of C1-INH replacement during the acute phase is consistent with current management of Hereditary Angioedema, especially where early intervention is deemed optimal. Furthermore, the long-term treatment with prophylactic C1-INH has been also reported successful as promising preventive strategy for decreasing the attack rates and hospital admissions, which also support its utilization in HAE treatment. Bradykinin receptor antagonists such as icatibant are also a well proven easy option for acute attack treatment. The convenience of administering icatibant subcutaneously has definite advantages: the simplicity of dosing and better patient compliance. Nevertheless, the relative efficacy of bradykinin receptor antagonists to C1-INH products is still somewhat unclear, and more details are needed to distinguish their uses in different subtypes of patients.\u003c/p\u003e \u003cp\u003eThe new therapeutic methods such as genetic engineering and immunotherapy that play an important role in the development of future HAE treatment plans. Initial data for the treatment of HAE by gene therapy show that modification of the genetic error may lead to a long-term or definitive outcome. But these are still in developmental stage, nonetheless emerging therapies of this type are a step forward towards better treatment of HAE based on individual genetic makeup (Germenis et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Similarly, more-targeted agents such as monoclonal antibodies like lanadelumab has proven useful in low-frequent administration resulting to low frequency of attacks and hence good compliance and quality life among the patients. These treatments underscore the possibility of further refined and longer-term strategies to HAE management. The possibility to integrate mHealth applications and wearable technologies in HAE management has a particular potential for improving the patient involvement of early warning signs tracking. There are impressions from patients, which show that the use of tools, which allow monitoring one\u0026rsquo;s activity and initiating timely actions, is useful. But as indicated earlier and also evidenced by this paper, real-life statistics documenting the usefulness of mHealth applications to HAE management remain scarce, which means that more research has to be conducted in this field.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003e\u0026bull; Future Research Directions\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe results of this study underscore several critical areas where further research is warranted: Comparative Studies of C1-INH and Bradykinin Receptor Antagonists: Since both the product and the drug are crucial in managing the acute attack, future research needs to compare C1-INH replacement therapy and bradykinin receptor antagonists in other HAE patients. Such studies should incorporate not only effectiveness, but attack type, the patients\u0026rsquo; perspective and cost, because this fills a definite gap by allowing the clinicians to better understand the best strategies in terms of treatment selection in reference to each patient\u0026rsquo;s condition.\u003c/p\u003e \u003cp\u003eLong-Term Safety and Efficacy of Gene Therapy: However, the current availably gene therapies in the treatment of HAE are still in their experimental stage and more and satisfactory studies are required to determine the safety, efficacy and general ethical consideration of the entire concept of Gene therapy. This makes it necessitous to differentiate between curative and symptomatic potentials of gene therapy as the method is designed to address the genetic background of HAE. Further study should also be done on patient perceptions about Gene Therapy and any limitations to its implementation including cost, availability and culture.\u003c/p\u003e \u003cp\u003eOptimization of Monoclonal Antibodies for Prophylactic Use: While using monoclonal antibodies in the management of HAE becomes increasingly popular, there is a need for more research into dosing schedules, costs required for this treatment, and efficacy of the said antibodies when it comes to treatment of various symptoms of HAE. Moreover, there was some research that compared monoclonal antibodies with conventional treatments, which could also have important information on how to use these new treatments individually in clinical practice.\u003c/p\u003e \u003cp\u003eDevelopment and Evaluation of mHealth Applications: Another nice opportunity for future investigation of mHealth applications is their ability to help patients with HAE monitor their symptoms, take medications as prescribed, and respond to emergencies. Further research should aim at creating new mHealth applications oriented to HAE management and offering strong evidence by including randomized controlled trials. These studies should also include: the satisfaction of users, data privacy and protections or the possibilities of enhancing patient care by use of mHealth applications.\u003c/p\u003e \u003cp\u003eFeasibility and Impact of Wearable Attack Detection Devices: In light of such development in wearable technology the idea of an HAE attack detector bracelet or similar devices is highly appealing. Future research should focus on finding better ways to describe algorithms to diagnose signal features that are indicative of an impending attack; reliability studies, compliance and effectiveness research. However, other crucial factors should also be extended, like ethical and social implication like; privacy of the data to be collected and the stigma that comes with wearing of medical devices.\u003c/p\u003e \u003cp\u003eExploration of Medical Alert Jewelry for HAE: In addition to attack detection devices, the importance of medical alert jewelry in the management of HAE deserves more investigation. Whether such devices form helpful intervention tools during emergencies that affect response times and patient outcomes may also be determined. Current studies could also investigate the users\u0026rsquo; preferences with regard to the design of the CDS, its functionality and compatibility with electronic health records. Addressing Global Disparities in HAE Diagnosis and Care: Therefore discrepancies in diagnosing and treatment accessibility among different countries in future studies should be considered. Ongoing research studies could involve discovery of cheap and efficient methods of diagnosing or treating HAE so that the disease could be managed in every corner of the world without discriminative outcomes.\u003c/p\u003e"},{"header":"6. Conclusion","content":"\u003cp\u003eThis systematic review of Hereditary Angioedema and its clinical presentation shows that there are research and therapeutic developments in this rare hereditary disorder that warrants future research and additional study. Due to multiple organ involvement and associated deficiency or dysfunction of C1 inhibitor, this condition has a course characterized by potentially life-threatening angiopericyte proliferation episodes of swelling with peripheral edema occurring in 45% of patients, abdominal pain in 30%, facial edema in 15% and laryngeal edema in 10%. The distribution pattern of HAE is broad and highlights the importance of individual management plans for this disease. The current treatment platforms have significantly developed with C1 Esterase Inhibitor (C1-INH) concentrates noted as the mainstay of HAE management. These concentrates have shown unsurpassed effectiveness in affording both acute episodes and chronic prevention and management, thus enhancing the quality of life of these patients. The use of bradykinin receptor antagonists and particularly icatibant has replaced the former with the benefits of subcutaneous application resulting in increased patient compliance and satisfaction. This approach of using both of them has brought about a revolution in the management of HAE providing patients with this disease with better copul flexibility in their medication. Newer therapies like monoclonal antibodies, and gene therapy are considered some of the second generation of therapies likely to define HAE management. However, they all conceal certain long-term safety and efficacy profiles, which nevertheless look very promising during pilot trials. A potential of gene therapy as the therapy targeting a cause of HAE is inspiring; however, great gaps of knowledge about the applicability and outcomes of gene therapy are remained. On the same note, there is a great potential for enhancing attack prediction and managing the care of patients through incorporating digital health care technology and smart monitoring devices into the care delivery system.\u003c/p\u003e \u003cp\u003eHowever, several issues regarding HAE management remain up to this date. The open-endedness of the attack, the inflammation variation of probable symptoms, and the severe consequences make the disease a subject of further investigation for more effective treatment solutions that can be developed. This shows that costs, availability of treatments, and the necessity of individual approaches are the burning issues to provide best possible treatment. In addition, the lack of information about relative effectiveness of examined interventions and the long term safety of newer treatments supports the need for additional clinical trials. In the future, it seems that the development in the management of HAE is the direction of continued advancement. Use of new conception in drug delivery system, practice of individualized medicine and merging of digital health solutions may promisingly expand the list of effective and patient-oriented therapeutic management. However, further progress in treatment of HAE will continue to depend on research endeavors especially in trying to more fully understand how different patients respond to various therapies, refining prophylactic approaches and finding better value therapies for this condition. The aim however stays focused on enhancing patients\u0026rsquo; quality of several facets of their life through highly individualized, holistic, medical and supportive interventions based approaches, to manage effectively this difficult genetic disorder in the short term as well as the long term perspectives.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other financial support were received for conducting this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003e not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBasant Kumar and Rashmi Dwivedi conceptualized the study and wrote the main manuscript text.Ahmed Abdullah Salim Humaid Al Lamki and Maryam Mohamed Ibrahim Al Balushi conducted the literature review and data analysis.Sandeep J and Hothefa Jassim prepared figures and tables.Afaq Ahmed contributed to the methodology and statistical analysis.All authors reviewed and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAabom, A., Bygum, A., \u0026amp; Koch, C. 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Expert Opinion on Pharmacotherapy, \u003cem\u003e17\u003c/em\u003e(1), 27\u0026ndash;40. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1517/14656566.2016.1104300\u003c/span\u003e\u003cspan address=\"10.1517/14656566.2016.1104300\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hereditary angioedema, C1 esterase inhibitor, bradykinin receptor antagonists, clinical manifestations, treatment strategies, personalized medicine","lastPublishedDoi":"10.21203/rs.3.rs-6245901/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6245901/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHereditary Angioedema or HAE is a rare autosomal dominant disease leading to three major types of acute swelling and is known to be triggered by C1 esterase inhibitor deficiency. The purpose of this systematic review was to summarize the key clinical features of HAE and to compare and analyze the available management options and potential new management prospects. For this study, their evaluation of cases showed that 45% of our HAE patients present with peripheral edema and 30% with abdominal pain, 15% with facial swelling, and 10% with larynx edema. The review of the treatment\u0026rsquo;s effectiveness showed that C1-INH replacement therapy forms the mainstay of HAE management and proved to deliver great success both, in acute attack management and long-term prevention. H2 Subcutaneous Bradykinin receptor antagonists were also established as an effective form of treatment which is quite reliable and more acceptable by the patients. The study evidences suggest that newer interferences, such as monoclonal antibodies and gene therapy, may hold significant potential in the course of HAE treatment, although additional investigations should provide definitive information related to the safety and efficacy in the long-term management of disease. The use of technologies in smart monitoring for health, and Integrated Digital Health System has become important tool to detect early attacks and for better results. In detailing the results, differences in treatment strategies also highlight how HAE attacks are difficult to predict and how clinical manifestations of the disease could be different from one patient to the other. The review also pointed out prominent limitations of current research, such as the comparison of the effectiveness between the newer treatments and the costs of administering these new treatments. Collectively, these conclusions support the notion that much advancement has taken place in the management of HAE and yet there remains much potential for optimizing the HAE patient\u0026rsquo;s care by development of better diagnostic, treatment and patient-completed and integration of the corresponding advanced technologies. Future concerns should include further refinement of the costs of treatments, the continued fine-tuning of prophylaxis, and long-term safety assessment of the newer therapies. These findings further knowledge in the management of HAE and offer useful guidelines in the management of HAE for health professionals.\u003c/p\u003e","manuscriptTitle":"Clinical manifestations of hereditary angioedema: a systematic review of treatment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-13 12:13:17","doi":"10.21203/rs.3.rs-6245901/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"df709f41-bcd9-45a6-8d53-74867f75d57f","owner":[],"postedDate":"May 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-23T14:08:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-13 12:13:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6245901","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6245901","identity":"rs-6245901","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}