Current characteristics associated with hereditary angioedema attacks and treatment: The home infusion based patient experience

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Raffi Tachdjian, M.D., M.P.H.,1 Aleena Banerji, M.D.,2 Autumn Guyer, M.D.,2 and Tricia Morphew, M.S.3

ABSTRACT This article presents a current perspective on the characteristics of hereditary angioedema (HAE) attacks and treatment as captured by a home infusion service. Retrospective data on 158 HAE patients who were enrolled in this acute treatment program were analyzed for factors surrounding an attack. The majority of patients had a high level of disease severity at baseline (88%), with a higher than expected likelihood of having a positive family history (87.8%). The most likely times for patients to call for home treatment were just before and during working hours (6:00 A.M.–5:00 P.M.). Eighty-three percent had more than one alternate mode of medication. Factors associated with a severe attack included an overall severe rating of HAE attacks in the previous year, an abdominal attack alone or a combination of peripheral and abdominal attacks versus a peripheral attack alone, and the use of two doses rather than one for treatment of the current attack. Average time to relief onset was 43.5 minutes. One dose of ecallantide was sufficient to treat the majority of attacks, and a second dose was needed in 23.6% of patients experiencing a severe attack. However, patients who reported both a severe attack rating during the previous year and experiencing only a peripheral current attack were more likely to experience a severe current attack. Acute treatment paradigms for HAE remain diverse. Understanding factors driving these decisions could help alleviate the overall burden of this disease and help overcome some of the challenges faced by the patients and their caretakers and improve their quality of life. Enhanced capture and analysis of prodromal factors in future studies should help us further alleviate the burden of this disease. (Allergy Asthma Proc 36:151–159, 2015; doi: 10.2500/aap.2015.36.3832)

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ereditary angioedema (HAE) is a rare autosomal dominant disease, in which patients develop swelling that typically occurs in the cutaneous tissues (such as extremities or face), abdomen, and larynx.1 The swelling gradually progresses over 12–24 hours and may last for 2–5 days.2 Attacks are unpredictable and can occur without warning and with variable severity.3 Approximately 25% of cases are believed to be de novo mutations without any family history.4 In 87– 96% of patients, a prodrome precedes the attack and may be characterized by a tingling sensation, erythema marginatum, substantial fatigue, or local discomfort.1,2,5 Many of the medications used for allergic angioedema, such as antihistamines, are neither indicated

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From the 1University of California, Los Angles, Los Angeles, California, 2Harvard Medical School, Boston, Massachusetts, and 3Morphew Consulting LLC, Los Angeles, California R. Tachdjian is a consultant and advisor for Dyax and Shire. A. Banerji has received grants and honorariums from Dyax, Shire, Biocryst, CSL Behring and Salix. T. Morphew is a consultant for Dyax. A. Guyer has no conflicts of interest to declare pertaining to this article Supplemental data available at www.IngentaConnect.com Address correspondence to Raffi Tachdjian, M.D., M.P.H., University of California, Los Angeles, School of Medicine, 1301 20th Street, Suite 220, Santa Monica, CA 90404 E-mail address: [email protected] Copyright © 2015, OceanSide Publications, Inc., U.S.A.

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nor useful in treating HAE attacks.6 Before recently Food and Drug Administration (FDA)–approved effective therapies, the risk of mortality from laryngeal attacks resulting in asphyxiation was significant.7,8 Despite the advent of new treatment modalities, HAE continues to have a negative impact on a patient’s quality of life,9,10 and our understanding of the burden of this disease remains poor.11–13 The FDA has recently approved five agents (two plasma-derived and one recombinant C1 esterase inhibitor concentrates, ecallantide, and icatibant) to treat HAE attacks, with optimal therapy based on the patient’s individual needs.14 –18 Since the availability of these therapies, international guidelines and recommendations have emerged to help manage this condition.19,20 However, inconsistent acute treatment approaches have called for investigation of factors affecting adherence to current recommendations.21 One acute treatment option, ecallantide (a kallikrein inhibitor), is associated with anaphylaxis in 2.7% of patients treated subcutaneously in clinical trials.22 Because of this risk, the FDA requires ecallantide to be administered by a health care professional. A unique treatment option has therefore emerged for this drug, where an HAE patient experiencing an attack gets treatment from a home infusion company.23 Nursing data collected from the home infusion companies pro-

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the reference level for each factor was reported along with the corresponding 95% confidence interval based on univariable models and a fully adjusted multivariable model. An additional stepwise procedure that included testing of all potential two-way interaction effects determined characteristics most predictive of a severe attack. This modeling procedure was repeated in examination of time to relief onset in the subset of patients treated from July to December 2012, when routine collection of this outcome measure was obtained. A forest plot was generated to describe factors included in the final model predicting a severe attack using software Forest Plot Viewer Version 1.00, descriptive statistics were calculated using SPSS Version 18.0, and mixed modeling procedures were run using SAS Version 9.2 (Cary, NC).26

vide a unique opportunity to evaluate the current state of the burden of illness in HAE patients.24 This article is an analysis of demographics, attack characteristics, treatment regimens and response, and nursing service performance in patients experiencing HAE attacks. METHODS Study Population and Design These data are an accumulation from the Walgreens Home Infusion Pharmacies and Sentara Home Infusion Pharmacy of Virginia.23 To be eligible for services, patients had to carry a primary diagnosis of 277.6 according to the ICD-9, which codes for “Other deficiencies of circulating enzymes; hereditary angioedema.” Patients deemed eligible for treatment by the provider completed a Home Infusion Services form, and a 30-mg dose of ecallantide was shipped to the patient’s home or preferred treatment site. Our study population was restricted to those who experienced an HAE attack and elected to use this on-demand nursing service. Considerations included, but were not limited to, patient safety for home administration, geographic location, and distance from an emergency department. Laryngeal attacks did not qualify for home infusion services, and the patients were strictly instructed to seek emergency medical services for laryngeal attacks. This study reports on adult patients who received treatment during the period spanning from September 24, 2011 to December 31, 2012. Deidentified data were provided to investigators and included elements specific to the attack, as well as the time elements for patient symptoms, nursing service measures, and treatment response. Time to onset of relief was measured as in prior studies,25 although it was known in 80% of visits. Additional measures included patient demographics, attack location, doses of ecallantide used to treat the attack, patient-assessed severity of the current attack, overall severity of swelling during the previous year period, alternate therapies used to treat prior attacks, and family history (known in 83% of visits).

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Patient Characteristics Approximately 15 months of data were available for 158 HAE patients enrolled in the home infusion service. Of those patients, 71.3% were women, with an average age of 38.3 years at the first visit and with 88% reporting an overall severity of attacks as moderate to severe in the previous year (Table 1). Of the 142 patients for whom HAE treatment information was available, 35.9% reported androgen/steroid use, 30.3% reported prophylactic C1 esterase inhibitor use as alternate medication, and 9.2% reported other nonindicated medication as alternate therapies, and up to 16.9% had no concomitant or indicated alternative therapies (Table 1). Seventy-four percent of patients used the home infusion service more than once, 76.4% of attacks were treated with only one dose of ecallantide, and there was a median interval of 8 days between home infusion services. The rate of peripheral attacks alone was 36.1%, followed by only abdominal ones (32.3%), and a combination of peripheral and abdominal attacks (28.5%). Of all these attacks, 3.2% included a component of laryngeal edema (Table 1). Finally, among the 114 patients who had responded, 87.7% reported a family member with HAE (Table 1).

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Statistical Analysis Demographic and clinical characteristics of the study population were described in terms of percent with the defined trait of the total number of patients or visits (factor dependent) for categorical factors. Mean (SE) and interquartile range (25th and 75th percentiles) provided descriptive information for continuous variables that were distributed normally or showed departures from normality, respectively. Examination of factors associated with a severe attack used generalized linear mixed modeling procedure.26 The likelihood of a severe attack for the respective category compared with

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Home Nursing Visit Characteristics Although nursing visits were equally distributed across most months after the initial offering in 2011, attacks were less likely to occur on Friday and Saturday versus other days of the week (␹2(1 df) ⫽ 20.9; p ⬍ 0.01; Fig. 1). Patients called in the morning (6:00 –11:59 A.M.) or afternoon hours (12:00 –17:59 P.M.) 33 and 34% of the time, respectively, whereas calls from 12:00 midnight to 6:00 A.M. occurred only 9% of the time (Fig. 1).

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Table 1 Characteristics of adult patients who received the home infusion intervention during a 15-mo period (September 24, 2011–December 30, 2012) Patients, n (valid %) or Mean (SE)

Overall n ⴝ 158 Patients

Age at first visit (range, 18–70 yr), yr 18–20 20–29 30–39 40–49 50⫹ Female Overall severity of swellings, year prior 1 Mild or less 2 Moderate 3 Severe Alternate acute therapies, valid n ⫽ 142 (more than one category possible) Androgens/steroids Epinephrine C1inh (acute) C1inh (prophylactic) Fresh frozen plasma Icatibant Other meds ”None” or “N/A” listed No. of alternate therapies listed, median (IQR) None or N/A One therapy only (1–7 above) More than one therapy (1–7 above) No. of home interventions during study period, median (IQR) One Two Three or more Visits (home interventions), n (valid %) or mean (SE) Attack location Abdominal only Peripheral only Abdominal ⫹ peripheral Laryngeal (any combination) Current attack severity before treatment* 1 Mild 2 Moderate 3 Severe One dose of ecallantide used to treat attack Time to relief onset (min)#§ Time between home infusion interventions (days)¶ median (IQR)

38.3 yr (1.17) 12.1% 19.1% 17.8% 27.4% 23.6% 71.3%

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11.9% 23.8% 64.2%

35.9% 15.5% 15.5% 30.3% 6.3% 13.4% 9.2% 16.9% 1 (1–2) range, 0–7 16.9% 54.9% 28.2% 4 (1–9) range, 1–70 25.9% 12.7% 61.3% n ⫽ 1177 visits 32.3% 36.1% 28.5% 3.2%

10.9% 45.3% 43.9% 76.4% 42.3 min (4.7) 8 days (3–20) Range, 0.07–275 days

*Patient assessed severity of current acute attack. #Time to relief onset ⫽ (time of relief ⫺ time of dose 1). One extreme outlier of 8 hr removed. §Estimated mean and SD based on SAS mixed modeling procedure to account for repeat measures (visits) within patient (covariance structure specified as type ⫽ unstructured). ¶Examined in patients with multiple interventions (visits by nurse). C1inh ⫽ C1 esterase inhibitor; IQR ⫽ interquartile range (25th and 75th percentiles).

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Association with Severe Attacks Factors associated with a severe attack included (1) an overall severe rating of HAE attacks in the previous year (p ⬍ 0.01), (2) an abdominal attack alone or a combination of peripheral and abdominal attacks versus a peripheral attack alone (p ⬍ 0.01), and (3) the use of two doses rather than one for treatment of the current HAE attack (p ⬍ 0.01; Table 2 and Fig. 2). A test for two-way interaction revealed that overall severity of swelling in the previous year was related to current attack severity, but only in patients with peripheral attacks (Fig. 2). Time to Relief Onset Average time to relief onset was 43.5 minutes. In a subanalysis, the mean time to relief onset in attacks

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Figure 1. Description of operations during a 15month study period. Distribution of total nurse visits per month, day of week attack occurred, and time of patient call are shown.

requiring one dose was 36 minutes, and for those requiring a second dose it was 67 minutes (Table 3). In the subset of 110 patients who received 405 home visits from July to December 2012, 74.1% reported improvement of symptoms and 25.2% showed no change. A severe rating of symptoms at baseline was associated with the most improvement after treatment (Online Supplement Table E1). DISCUSSION This analysis contributes new insight into HAE attack characteristics and related treatment paradigms from a home nursing program perspective. With each patient observed for 1 hour after drug administration, this is the first real-time data capture measuring time to relief onset and factors associated with HAE attacks.

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Table 2 Examination of factors associated with a severe attack (mixed modeling procedure), unadjusted and adjusted for all factors listed Outcome: Severe Attack# n ⴝ 158 Patients, 1177 Visits Overall Age at home visit, yr ⬍20 20–29 30–39 40–49 ⱖ50 Gender Male Female Patient home intervention§ One Two Three or higher Overall severity of swellings, previous year Less than severe Severe Attack location¶ Abdominal only Peripheral only Combination Time of patient call (attack) 0:00–5:59 (A.M., early morning) 6:00–11:59 (A.M., morning) 12:00–17:59 (P.M., afternoon) 18:00–23:59 (P.M., nighttime) Doses used to treat attack One Two

Unadjusted OR (95% CI)

Adjusted OR (95% CI)

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0.51 (0.22, 1.16) 0.84 (0.41, 1.71) 0.88 (0.43, 1.78) 0.61 (0.32, 1.16) Reference Reference 1.61 (0.95, 2.70)

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0.85 (0.57, 1.28) 1.05 (0.67, 1.65) Reference

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0.68 (0.30, 1.56) 1.03 (0.51, 2.08) 0.91 (0.45, 1.83) 0.66 (0.35, 1.26) Reference Reference 1.33 (0.78, 2.26) 0.90 (0.58, 1.39) 1.03 (0.64, 1.67) Reference

Reference 2.32 (1.41, 3.81)**

Reference 1.88 (1.13, 3.12)*

2.97 (1.97, 4.48)** Reference 3.41 (2.34, 4.96)**

3.11 (2.02, 4.80)** Reference 3.25 (2.19, 4.81)**

1.35 (0.79, 2.31) 1.10 (0.76, 1.61) 1.29 (0.91, 1.85) Reference

1.38 (0.78, 2.42) 0.99 (0.67, 1.47) 1.15 (0.79, 1.66) Reference

Reference 2.17 (1.51, 3.11)**

Reference 2.19 (1.49, 3.23)**

GLIMMIX procedure with test for effect significant, *p ⬍ 0.05 and **p ⬍ 0.01. #Patient assessed severity of current acute attack. §Number of home interventions during the study period. ¶Laryngeal attacks not considered for nursing service. GLIMMIX ⫽ generalized linear mixed modeling; OR ⫽ odds ratio.

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The overall goal of this study was to assess the burden of illness as it is manifested in the era of new treatment modalities, and the results may shed light on improving our understanding of its pathophysiology. It appears that the majority of HAE patients enrolled in this program have a high level of disease severity at baseline (88%), with a higher than expected likelihood of having a positive family history (87.8%). A significant number of patients reported having androgens/ steroids or epinephrine injectors; treatment modalities deemed ineffective in preventing or treating HAE attacks.27 Although 16.9% of the patients in this database reported not using any medication for attacks, 9.2% reported other off-label medications as alternate therapies. Nonetheless, the great majority of these patients

(83.1%) had more than one alternate mode of medication. As such there needs to be further exploration of (1) factors affecting access to therapeutics options, (2) effects of a given drug’s possible variability between type and location of attack within and between patients, (3) understanding and communication of attack characteristics and optimal treatment regimens among prescribers and how they influence compliance and adherence by the patient, and (4) psychosocial and emotional factors that may influence the types and frequencies of medications used. One thing that remains certain is that the acute treatment paradigms are as diverse as the presentation of the disease itself. The most likely times for patients to call for home treatment were just before and during working hours

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Figure 2. Factors associated with a severe attack (mixed modeling procedure), after examination of all potential confounding and two-way interaction effects assessed using stepwise modeling procedure. Doses used to treat attack, overall severity (year before consultation), attack location (current), and overall severity (year prior)* attack location (current) are shown. Interaction term between overall severity of swelling in prior year and attack location are borderline significant (p ⫽ 0.081) and retained.

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(6:00 A.M.–5:00 P.M.). This information may be useful to the treating professionals and infusion services in terms of preparedness and resource allocation. It may also help in developing predictive models for attacks and to understand prodromes leading to HAE attacks.28 Additionally, Fridays and Saturdays accounted for a significantly less propensity to call the home infusion services. In a different study, prodromes were experienced hours before onset of angioedema in ⬎82% of patients, thus making identification of such warning signs important in faster onset of treatment and relief.29 There may be reporting bias because of calls more likely to be made during waking hours and certain days of the week, but there may also be significance in the expression of symptoms during wakeful times, with a decreased likelihood of attacks to begin during the late night/early morning hours or days leading into the weekend. Therefore, the effects of the circadian rhythm and other markers for inflammation deserve further investigation. In a study with a group of 179 patients using ecallantide for HAE, a second dose was used in 12% of attacks.30 In this same study, multivariate analysis showed only peripheral attacks being correlated with a second dose requirement. Our study revealed that 23.6% of attacks required a second dose. However, patients who reported both a severe attack rating during the previous year and experiencing only a periph-

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eral current attack were more likely to experience a severe current attack. This dependent relationship with attack severity in the previous year was not observed for abdominal alone or a combination of abdominal and peripheral attacks. The average time to relief onset was ⬍1 hour (43.5 minutes), with a higher likelihood of attack severity improvement among those with a baseline severe rating of the disease. In other drug studies, earlier administration of a C1 esterase inhibitor concentrate and icatibant (a bradykinin-2 receptor antagonist) independently was shown to shorten time to relief onset.31,32 Emotional and psychosocial factors may affect the timing and severity of triggers, prodromes, swelling and location, pain, need for an additional dose, and the time to relief onset.2 These same factors may affect the patient’s perception of the current attack, the decisions surrounding future attacks, and perhaps, ultimately, the patterns by which calls are placed to the home infusion service. Understanding these factors could help alleviate the overall burden of this disease and help overcome some of the challenges faced by the patients and their caretakers and improve the quality of life. Inherent in the shortcomings of a retrospective study such as this are self-selection of patients into this program and recall bias. For that reason we do not have further details surrounding rebound of attacks and relapses as in other studies. We did not have access to

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Table 3 Examination of factors associated with time to relief onset (mixed modeling procedure), unadjusted and adjusted for all factors listed Outcome: time to relief onset n ⴝ 158 Patients, 1177 Visits

Time to Relief Onset (min) Estimated Mean (SE) Unadjusted

Overall Age at home visit, yr ⬍20 20–29 30–39 40–49 ⱖ50 Gender Male Female Patient visit# One Two Three or higher Overall severity of swellings, year prior Less severe Severe Current attack severity before treatment# Less severe (mild–moderate) Severe Attack location Abdominal only Peripheral only Combination Time of patient call (attack) 0:00–5:59 (A.M., early morning) 6:00–11:59 (A.M., morning) 12:00–17:59 (P.M., afternoon) 18:00–23:59 (P.M., nighttime) Doses used to treat attack One Two

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42.3 min (4.7) 34.6 (6.6, 62.5) 43.1 (18.7, 67.6) 48.2 (27.9, 68.4) 38.2 (20.7, 55.7) 44.2 (26.2, 62.1)

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45.7 (27.9, 63.5) 40.9 (30.1, 51.8)

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43.5 min

38.6 (10.0, 67.2) 44.9 (19.9, 70.0) 51.2 (30.2, 72.2) 43.8 (25.6, 61.9) 37.7 (18.1, 57.2) 47.5 (28.7, 66.4) 41.7 (30.5, 52.9)

40.9 (17.9, 64.0) 40.0 (13.8, 66.1) 43.0 (32.4, 53.6)

45.4 (21.3, 69.6) 42.5 (14.9, 70.2) 43.1 (32.4, 53.9)

36.3 (19.3, 53.3) 45.4 (34.3, 56.6)

38.5 (20.7, 56.3) 45.3 (34.1, 56.5)

41.8 (29.8, 53.8) 43.5 (29.8, 57.2)

44.2 (31.8, 56.6) 42.3 (28.0, 56.6)

40.5 (23.7, 57.4) 42.2 (26.3, 58.2) 43.9 (29.7, 58.1)

43.2 (25.9, 60.6) 42.4 (25.2, 59.6) 44.2 (29.6, 58.9)

44.3 (14.9, 73.8) 43.2 (27.5, 58.9) 43.1 (27.6, 58.6) 40.4 (22.6, 58.3)

45.5 (14.7, 76.4) 43.2 (27.2, 59.1) 43.3 (27.7, 58.9) 43.0 (24.7, 61.4)

35.5 (25.1, 46.0)** 64.3 (45.3, 83.3)

36.0 (25.2, 46.8)** 67.1 (46.5, 87.6)

Mixed model type 3 test of effect significance, *p⬍ 0.05 and **p ⬍ 0.01; no factors significantly influenced average time to relief in unadjusted model (p ⬎ 05), with exception of doses used to treat attack. #Patient assessed severity of current acute attack. demographic data from other on-demand therapies and therefore can not provide a comparison with other populations.33,34 Only a subset of the patients had data on alternate therapies. Data captured on this subset also contained limited details surrounding circumstances under which medication was prescribed. For instance, epinephrine may have been provided as part of the anaphylaxis kit that comes standard with the ecallantide prescription or it could have been prescribed as a first-line treatment for an attack. Similarly, we do not have information on the alternate acute therapy indications such as androgen/steroids. For a

given patient this could have been used suboptimally as therapy for an HAE attack or as a more likely part of a prophylactic regimen. We also can not detect if the reported laryngeal attacks occurred after the nursing service was called for an abdominal or peripheral attack. This needs to be better communicated in the future, because laryngeal attacks do not meet home infusion service qualification criteria. Furthermore, migration of attacks poses a significant danger and needs to be addressed in future programming.1 Finally, the lack of detailed pain and emotional measures prevents a more thorough understanding of the psychological

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burden of this disease. Hence, the importance of psychosocial stressors and emotional factors seems to present an area of unmet need in this condition previously coined as angioneurotic edema.35 CONCLUSION In this study we present a current perspective of HAE attacks and treatment as captured by a home infusion service, along with characteristics that surround this program. An advantage of this service is that it follows the largest cohort of HAE patients being evaluated by a health professional at the time of an attack. Aside from the benefits gained by the patient’s access to home nursing during an HAE attack, this analysis should lead to optimized nursing preparedness and quality of response to patient calls. Recently, one of the main focal points has been to overcome the challenges in properly diagnosing these patients. This was attributed to the lack of medical community awareness, access to care limitations, and potential financial barriers to obtain proper diagnostic testing and treatment in place. We must now shift some of our efforts to ensure the use of indicated and effective treatment modalities, rather than other products as first-line or concomitant therapeutic agents for HAE attacks. Enhanced capture and analysis of these prodromal factors in future studies should help us alleviate the burden of HAE. Improvements in such data systems are still possible and desirable to enable capture in real time. Such a system must track patient and health care provider entry continuously and not just during attacks. This may, in turn, decrease overuse of concomitant therapies, improve effectiveness of indicated treatment, and optimize the quality of life and functional abilities of those affected.

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Current characteristics associated with hereditary angioedema attacks and treatment: the home infusion based patient experience.

This article presents a current perspective on the characteristics of hereditary angioedema (HAE) attacks and treatment as captured by a home infusion...
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