Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.

BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

Association of Variants Near the Bradykinin Receptor B2 Gene With Angioedema in Patients Taking ACE Inhibitors.

BACKGROUND: Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. OBJECTIVES: The aim of this study was to identify genetic factors associated with ACE inhibitor-associated angioedema. METHODS: A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors ≤180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model. RESULTS: The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor-treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor-treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 × 10-8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 × 10-9). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 × 10-3). We found that carriers of the risk allele had significantly lower systolic (-0.46 mm Hg per T allele; 95% CI: -0.83 to -0.10; P = 0.013) and diastolic (-0.26 mm Hg per T allele; 95% CI: -0.46 to -0.05; P = 0.013) blood pressure. CONCLUSIONS: In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with increased risk for ACE inhibitor-related angioedema.

Clinical Features and Disease Course of Primary Angioedema Patients in a Tertiary Care Hospital.

PURPOSE: To give a better understanding of primary AE, the clinical characteristics and the possible therapeutic approaches. BACKGROUND: Angioedema (AE) is a non-pitting, non-itching swelling of skin or mucosa. The symptom can become life-threatening if located in the airways. Primary (monosymptomatic) AE is a manifestation of several different diseases and the diagnosis is not always straight-forward. The aetiological and pathophysiological factors of primary AE are not completely clarified. There is a need for further investigation. PATIENTS AND METHODS: This was a retrospective cohort study of patients referred to an outpatient dermatology clinic in a tertiary care hospital for clinical assessment due to primary AE in the period from 1996 to 2014. RESULTS: A total of 315 patients were identified with primary AE. The most frequent subtype was idiopathic AE (42.5%) and the second most common was angiotensin-converting enzymeinhibitor (ACEi)-induced AE (31.1%). Three patients were diagnosed with hereditary AE and one patient was diagnosed with acquired C1-inhibitor deficiency. At least 107 (34.0%) patients had established histaminergic AE. More than 1/3 of the patients were treated in an emergency room or hospitalized due to AE. A 98.1% of patients had experienced AE in the head and neck area. Seven patients were in the need of acute airway intervention. Six of these had ACEi-induced AE. Female sex and smoking were found to be risk factors for developing AE. CONCLUSION: The most frequent diagnoses were histaminergic-, non-histaminergic idiopathic AE and ACEi-induced AE, whereas complement C1-inhibitor deficiency was rare. Histaminergic AE made up a substantial group of patients with primary AE. Even though there are different pathophysiological causes of AE, many cases have overlapping clinical manifestations, which make diagnosis and treatment difficult.

Incidence of post-tonsillectomy haemorrhaging in Denmark.

INTRODUCTION: Tonsillectomy is one of the most common procedures in the field of ear, nose and throat procedures. In 2012, the annual incidence in Denmark was 129.4 per 100,000 inhabitants. A common complication is post-tonsillectomy haemorrhaging (PTH). The overall PTH rates vary widely among studies ranging from 0.5% to 33%. METHODS: This was a nationwide open-population, retrospective and registry-based cohort study in Danes who underwent tonsillectomy complicated by PTH in hospitals and private otorhinolaryngology (ORL) offices in the period from 1991 to 2012. RESULTS: In the 1991-2012 period, a total of 177,211 tonsillectomies were performed among which 9,221 had a registered PTH (rPTH) (5.2%). The annual incidence rate of rPTH increased from 3% in 1991 to 13% in 2012 (p less-than 0.05). Males aged 20-40 years had a significantly higher risk of rPTH with the highest increase in rPTH incidence rates from 9.0% in 1998 to 16.4% in 2012 (p less-than 0.05). Approx. 12% had a primary rPTH within the first 24 hours; the maximum incidence of rPTH was on day six (14%). CONCLUSIONS: The rate of rPTH increased from 1991 to 2012 in hospitals and in private ORL office settings alike. There was a significantly higher rate of rPTH in the age group of 20-40 years and a significant geographical difference in rPTH. The highest risk of rPTH was observed on the day of surgery and on day six. TRIAL REGISTRATION: The Danish Data Protection Agency (record number 2012-41-0158) approved this study. FUNDING: The Olga Bryde Nielsen Foundation and H. Skouby & E. Skouby's Foundation supported this study financially.

Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.

Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10-5). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10-8). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05-2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema.

Correction: Genetic susceptibility to angiotensin-converting enzyme-inhibitor induced angioedema: A systematic review and evaluation of methodological approaches.

[This corrects the article DOI: 10.1371/journal.pone.0224858.].

Genetic susceptibility to angiotensin-converting enzyme-inhibitor induced angioedema: A systematic review and evaluation of methodological approaches.

Angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II which causes vasoconstriction. ACE inhibitors reduce blood pressure by inhibiting ACE. A well-known adverse drug reaction to ACE inhibitors is ACE inhibitor-induced angioedema (ACEi-AE). Angioedema is a swelling of skin and mucosa, which can be fatal if the airway is compromised. We have performed a systematic review of the evidence suggesting that genetic polymorphisms are associated with ACEi-AE and evaluated the methodological approaches of the included studies. The Cochrane Database of Systematic Reviews, Google Scholar, and PubMed were searched. Studies investigating the association between genetic markers and ACEi-AE were included. The Q-genie tool was used to evaluate the quality of the study methodologies. Seven studies were included. With the exception of one whole genome study, all of the included studies were candidate gene association studies. Study quality assessment scores ranged from 36 to 55. One study was found to be of good quality, suggesting that the detected associations may be unreliable. The inferior quality of some studies was due to poor organization, lack of analyses and missing information. Polymorphisms within XPEPNP2, BDKRB2-9/+ 9 and neprilysin genes, were reported to be associated with increased risk of ACEi-AE. However, due to low quality, these associations need to be confirmed in larger studies.

Acquired complement C1 esterase inhibitor deficiency in a patient with a rare SERPING1 variant with unknown significance.

Angioedema (AE) is caused by a wide range of diseases and pharmaceuticals; it can become life-threatening when located to the airways. Patients with deficiency or malfunction of complement C1 esterase inhibitor (hereditary or acquired) experience recurrent AE due to an accumulation of the vasoactive mediator bradykinin (BK). Complement C1 inhibitor normally decreases BK production, so a reduced function hereof causes increased levels. The diagnosis of hereditary or acquired AE can be difficult due to similarities to allergic reactions (swelling, abdominal pain, rash). We describe a 35-year-old man presenting with upper-airway AE progressing rapidly and promptly required cricothyroidotomy. Complement and autoantibody screening together with sequencing of SERPING1 were performed and gave the diagnosis of acquired complement C1 esterase inhibitor deficiency. The patient is unusual to have this disease before the age of 40 years. No associated comorbidities were found. It is important to know that antiallergic medication is not effective in BK-mediated AE.

Angiotensin II receptor blockers are safe in patients with prior angioedema related to angiotensin-converting enzyme inhibitors - a nationwide registry-based cohort study.

BACKGROUND: It has long been suggested that angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (AT2s) have some degree of 'cross-reactivity' in causing angioedema. Therefore, caution has been advised when switching patients with ACEi-related angioedema to an AT2. OBJECTIVES: To clarify whether AT2s can be used safely in patients with a history of angioedema during ACEi treatment and to estimate the incidence rate of angioedema in patients subsequently treated with other antihypertensive drugs (beta-adrenergic blockers, calcium channel blockers, thiazides and analogues) or no antihypertensives. METHODS: This is a nationwide retrospective registry-based cohort study of the Danish population during the period 1994 to 2016, and it uses Danish health registries. Propensity score adjusted and conventional proportional hazards regression models have been employed. RESULTS: A total of 1 106 024 ACEi users were identified. In total, 5 507 (0.5%) of these patients had experienced angioedema during ACEi treatment and were included in the study. The highest risk of angioedema recurrence was associated with continued ACEi use at an adjusted hazard ratio of 1.45 (95% CI, 1.19 to 1.78). An inverse association was found between AT2s and angioedema (adjusted hazard ratio, 0.39; 95% CI, 0.30 to 0.51) compared with other antihypertensives (adjusted hazard ratios, 0.77 to 0.97). CONCLUSIONS: Compared with other antihypertensive drugs, AT2s do not increase the incidence of angioedema in patients with previous ACEi-related angioedema.

ACE-Inhibitor Related Angioedema Is Not Sufficiently Reported to the Danish Adverse Drug Reactions Database.

PURPOSE: The primary objective of this study was to calculate the report rate of angiotensin-converting enzyme inhibitor-related angioedema (ACEi-AE). Secondary objectives were to determine factors suspected to affect the likelihood of ACEi-AE being reported and to investigate potential differences in angioedema risks between different ACEis. PATIENTS AND METHODS: Patient data from two cohorts comprising 176 patients with ACEi-AE were compared with report data from the Danish Adverse Drug Reactions Database, administered by the Danish Medicines Agency (DKMA). The study period was 1994-2015. Data were linked using unique personal identification numbers and birth dates. Cohort data and report data were compared with ACEi sales numbers from MedStat, an official database containing annual pharmaceutical drug sale data in Denmark. RESULTS: ACEi-AE was reported in two out of 176 cases resulting in a report rate of 1.1%, meaning that 98.9% of the cases were not reported. Since 1994, a total of 417 ACEi-AE reports were made to the DKMA. Fifty-eight percent of these were made by general practitioners or physicians with unknown workplaces and 35% by hospital staff. Enalapril and ramipril were the most sold ACEi's in the study period (40.3% and 42.6%, respectively). Enalapril was associated with 54.7% of ACEi-AE reports while ramipril was associated with 14.2%. ACEi substance received was known for 141 cohort patients, of which 53.9% were prescribed enalapril and 17.0% received ramipril. CONCLUSION: ACEi-AE was found to be severely underreported in Denmark, greatly limiting the available incidence data for this potentially life-threatening adverse reaction.

Corrigendum to "Assessment of 105 Patients with Angiotensin Converting Enzyme-Inhibitor Induced Angioedema".

[This corrects the article DOI: 10.1155/2017/1476402.].

A nationwide registry-based cohort study of incidence of tonsillectomy in Denmark, 1991-2012.

OBJECTIVE: To update tonsillectomy incidence rates in Denmark and identify whether the incidence rates vary between geographical areas in the country during the period 1991-2012. DESIGN: This was a retrospective nationwide cohort study using data from the comprehensive Danish patient registries. Data included surgical code, gender and date of birth, date and place of surgery. SETTING: Hospitals and private oto-, rhino-, laryngology (ORL) offices. PARTICIPANTS: Danes who underwent tonsillectomy in the period 1991-2012. MAIN OUTCOME MEASURE: Tonsillectomy. RESULTS: In the 22-year period, 177 211 tonsillectomies were conducted, and the overall incidence of tonsillectomy decreased significantly over time. The overall annual incidence of tonsillectomies decreased from 155.7 per 100 000 inhabitants in 1991 to 129.4 per 100 000 inhabitants in 2012. In 1991, 5.5% of tonsillectomies were performed in office settings, while in 2012, it had increased to 26.6% (P < .01). The highest incidence of tonsillectomy was found in children between 3 and 4 years of age (predominance of males, P < .01) and in 15- to 19-year-olds (predominance of females, P < .01). Each year, 0.44% of children underwent tonsillectomy, and by the age of 20, 7.7% of the Danish people has had a tonsillectomy. There were significant regional differences in the number of tonsillectomies. CONCLUSION: The incidence rate of tonsillectomies in Denmark decreased significantly in the study period, but with great regional variance.

Long-term follow-up and outcome in patients with recurrent respiratory laryngeal papillomatosis.

INTRODUCTION: Recurrent respiratory papillomatosis is characterized by wart-like lesions of the upper airway and is most frequently caused by human papillomavirus (HPV). The disease has significant impact on quality of life due to potential airway obstruction, dysphonia and the need for serial surgeries. The main objective of this study was to describe patient characteristics and long-term follow-up data in a Danish cohort with the disease. METHODS: The study was a longitudinal retrospective cohort-study using data from electronic medical records and a pathology database. RESULTS: A total of 61 adult and four juvenile patients were identified. The male-to-female ratio was 2.4. In the adult population, the mean age at onset was 45 years. The median number of surgeries was four (interquartile range: 2.8). The mean follow-up time was 8.7 years (range: 7 days-30 years). Three cases of malignant transformation were observed. In the juvenile population, the mean age of onset was 8.5 years (range: 3-12 years). The mean follow-up time was 11.5 years (range: 2-23 years), and the number of surgeries per year at risk was one/year. CO2-laser and microdebrider were the surgical techniques usually employed. 43% of histopathologic analyses could detect HPV infection (subtype 6 or 11). CONCLUSIONS: More males than females suffer from respiratory papillomatosis; age of onset was either in childhood or in mid-life. Use of CO2-laser or microdebrider was the preferred surgical approach in this cohort. FUNDING: none. TRIAL REGISTRATION: not relevant.

[A burned-out seminoma lymph node metastasis to the neck of a patient treated for colon cancer].

The incidence of metastases to the neck in testicular cancer is 4-15%, and in 5% of these cases the metastasis is the only symptom. We present a 57-year-old asymptomatic male, who had previously been treated for colon cancer. A routine PET-CT showed enlarged lymph nodes in the retroperitoneum and at the neck. A core needle biopsy from the lymph node at the neck contained malignant cells, but not from colon cancer. The lymph node was extirpated, and pathological analysis proved it to be a metastasis from a testicular seminoma. A burned-out seminoma was subsequently found in the patient's right testicle.

Assessment of 105 Patients with Angiotensin Converting Enzyme-Inhibitor Induced Angioedema.

Objective. To asses a cohort of 105 consecutive patients with angiotensin converting enzyme-inhibitor induced angioedema with regard to demographics, risk factors, family history of angioedema, hospitalization, airway management, outcome, and use of diagnostic codes used for the condition. Study Design. Cohort study. Methods. This was a retrospective cohort study of 105 patients with angiotensin converting enzyme-inhibitor induced angioedema in the period 1995-2014. Results. The cohort consisted of 67 females and 38 males (F : M ratio 1.8), with a mean age of 63 [range 26-86] years. Female gender was associated with a significantly higher risk of angiotensin converting enzyme-inhibitor induced angioedema. 6.7% had a positive family history of angioedema. Diabetes seemed to be a protective factor with regard to angioedema. 95% experienced angioedema of the head and neck. 4.7% needed intubation or tracheostomy. 74 admissions took place during the study period with a total of 143 days spent in the hospital. The diagnosis codes most often used for this condition were "DT783 Quincke's oedema" and "DT78.4 Allergy unspecified". Complement C1 inhibitor was normal in all tested patients. Conclusion. Female gender predisposes to angiotensin converting enzyme-inhibitor induced angioedema, whereas diabetes seems to be a protective factor.

Recurrent angioedema associated with pharmacological inhibition of dipeptidyl peptidase IV.

Angioedema (AE) of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to increased use of medications inhibiting the degradation of vasoactive peptides. Acquired angioedema related to angiotensin-converting enzyme inhibitors (ACEI-AAE) is well known, but other pharmaceutical agents also affect the degradation of bradykinin and substance P. We present a middle-aged man with recurrent episodes of severe AE of the oral cavity, hypopharynx and larynx due to pharmacological inhibition of dipeptidyl peptidase IV.

The Use of Plasma-Derived Complement C1-Esterase Inhibitor Concentrate (Berinert®) in the Treatment of Angiotensin Converting Enzyme-Inhibitor Related Angioedema.

Angioedema of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to pharmaceuticals influencing the generation or degradation of the vasoactive molecule bradykinin. Plasma-derived C1-esterase inhibitor concentrate is a well-established treatment option of hereditary and acquired complement C1-esterase inhibitor deficiency, which are also mediated by an increased level of bradykinin resulting in recurrent angioedema. We here present a case of severe angiotensin converting enzyme-inhibitor related angioedema (ACEi-AE) of the hypopharynx that completely resolved rapidly after the infusion of plasma-derived C1-inhibitor concentrate adding to the sparse reports in the existing literature.

How Not to Be Misled by Disorders Mimicking Angioedema: A Review of Pseudoangioedema.

BACKGROUND: Angioedema is a vascular reaction involving the lower dermis, subcutis and/or submucosal tissue and causing a temporary localized swelling in any part of the body. For many health care professionals, the diagnosis presents an ongoing challenge; several disorders may manifest with subcutaneous or submucosal swelling and falsely be assumed to be angioedema. The clinicians at the emergency department and in the immunology/allergy clinics must be skilled at recognizing the features of angioedema and its differential diagnosis. METHODS: The review is based on a literature search with specific indexing terms in PubMed, a review of bibliographies and the authors' clinical experience. RESULTS: The most essential diseases that mimic angioedema, the so-called pseudoangioedemas, will each be discussed and illustrated by clinical photos, pointing out key features that help clarify the diagnoses and differentiate these from classic angioedema. CONCLUSIONS: A variety of dermatologic conditions can cause swelling that resembles angioedema, some with a potentially fatal outcome if misdiagnosed. Knowledge of pseudoangioedema is fundamental in the emergency setting when handling patients with edema and should be kept in mind when assessing an atypical angioedema case.