Hereditary angioedema (HAE) is an inherited C1-inhibitor deficiency that affects 1 in 50,000 individuals in the United States.1 Acute HAE symptoms can be life-threatening and require emergency department (ED) care. Data on ED utilization since the introduction of new HAE therapeutics are limited. Furthermore, approximately half of acute HAE attacks present exclusively with abdominal symptoms.2 Abdominal symptoms can be challenging to diagnose, and mistaken diagnoses may lead to unnecessary radiologic examinations and surgeries.3 Although unnecessary abdominal imaging in HAE-diagnosed patients in the ED is frequently reported in case series,3 no studies have examined the overall prevalence in the ED. Our objective was to examine ED utilization and abdominal imaging ordered for patients with HAE.
We analyzed the 2015-2016 Nationwide Emergency Department Sample, a representative sample of approximately 20% of ED visits in the United States. Consistent with previous studies, International Classification of Diseases codes were used to identify HAE and controls.4 Previous studies used all other types of angioedema (angioedema) as controls because angioedema presents similarly to HAE in the ED, but management differs significantly.4 Utilization of abdominal computed tomography (CT) imaging, abdominal x-ray, and emergency airway intubation was examined (see Table E1 in this article’s Online Repository at www.jaci-inpractice.org).
TABLE E1.
ICD and Current Procedure Terminology codes identified
| Diagnosis | ICD code |
|---|---|
| Hereditary angioedema |
ICD-9; 277.6 ICD-10; D84.1 |
| All other types of angioedema |
ICD-9; 995.1 ICD-10; T78.3XXA, T78.3XXD, T78.3XXS |
| Imaging | Current Procedure Terminology code |
| Abdominal CT with contrast | 74160, 74170, 74177, 74178 |
| Abdominal CT without contrast | 74150, 74176 |
| Abdominal x-ray | 74000, 74010, 74020, 74022 |
| Emergency airway intubation | 31500, 31600, 31700 |
| Chest x-ray | 71010, 71020, 71030, 71035 |
ICD, International Classification of Diseases; ICD-9, International Classification of Diseases, Ninth Revision; ICD-10, International Classification of Diseases, Tenth Revision.
Logistic regression models adjusted for age (continuous), sex, and insurance payer examined differences in imaging patterns for patients with HAE versus patients with angioedema. Multivariable logistic regression models invoking stepwise selection were constructed to determine predictors of inpatient admission (dependent variable) during HAE versus angioedema ED visits. Models included sex (male/female); age (0-17/18-39/40-59/60+ years); household income (below/above median); health insurance type (private/public/none); admission on a weekend (yes/no); hospital region (Northeast/Midwest/South/West) and location (metropolitan/not metropolitan); and season (winter/spring/summer/autumn). Crude and adjusted odds ratios (ORs) and 95% confidence intervals (CI) were estimated. Geometric mean and total annual cost of ED care were generated. Linear regression models compared log-transformed, inflation-adjusted costs of patients with HAE versus patients with angioedema. All analyses were performed in SAS version 9.4 (SAS Institute, Cary, NC). P values were corrected for multiple dependent tests (k = 62) using the Benjamini-Hochberg approach.5
Data were captured from 56,219,413 (weighted frequency, 256,284,283) ED visits during the period 2015 to 2016, including 1917 (8924) visits of persons with HAE and 46,969 (215,356) visits of persons with angioedema. Based on previous estimates of HAE prevalence in the United States,1 the computed annual incidence of ED visits from our data is 55 visits per 100 persons with HAE each year. In multivariable logistic regression models invoking stepwise selection, ED visits in HAE versus angioedema occurred less often among older (adjusted OR [95% CI], 40-59 years: 0.52 [0.32-0.86], 60+ years: 0.25 [0.100.63]) and uninsured patients (0.44 [0.31-0.63]) and during the weekend (0.85 [0.74-0.97]) (Table I).
TABLE I.
Sociodemographic and clinical associations of ED visits among patients with HAE vs angioedema
| Variable | HAE diagnosisdc | Angioedema diagnosis | ||||||
|---|---|---|---|---|---|---|---|---|
| Weighted frequency | Prevalence (95% CI) | Weighted frequency | Prevalence (95% CI) | Crude OR (95% CI) | p | Adjusted OR* (95% CI) | p | |
| Sex | ||||||||
| Male | 3191 | 36.3 (28.3-44.2) | 96,228 | 44.7 (44.1-45.3) | 1.00 (reference) | — | † | † |
| Female | 5610 | 63.7 (55.8-71.7) | 118,966 | 55.3 (54.7-55.9) | 1.42 (1.01-2.00) | .09 | † | † |
| Age (y) | ||||||||
| <18 | 1621 | 18.4 (11.9-25.0) | 21,378 | 9.9 (9.2-10.7) | 1.00 (reference) | — | 1.00 (reference) | — |
| 18-39 | 3200 | 36.4 (26.9-45.9) | 43,268 | 20.1 (19.6-20.6) | 0.98 (0.63-1.52) | .91 | 1.17 (0.75-1.83) | .68 |
| 40-59 | 2455 | 27.9 (20.4-35.4) | 72,075 | 33.5 (32.9-34.1) | 0.45 (0.28-0.71) | .003 | 0.52 (0.32-0.86) | .03 |
| 60+ | 1525 | 17.3 (5.1-29.5) | 78,512 | 36.5 (35.7-37.2) | 0.26 (0.10-0.64) | .01 | 0.25 (0.10-0.63) | .01 |
| Income | ||||||||
| <50th %’ile | 4492 | 52.0 (39.5-64.4) | 127,678 | 60.3 (58.4-62.3) | 0.71 (0.44-1.16) | .29 | † | † |
| >50th %’ile | 4155 | 48.0 (35.6-60.5) | 83,908 | 39.7 (37.7-41.6) | 1.00 (reference) | — | † | † |
| Insurance status | ||||||||
| Private | 3256 | 37.0 (28.7-45.3) | 79,411 | 36.9 (36.0-37.8) | 1.00 (reference) | — | 1.00 (reference) | — |
| Public | 4967 | 56.5 (47.2-65.8) | 108,755 | 50.6 (49.6-51.6) | 1.11 (0.76-1.64) | .69 | 1.51 (1.08-2.12) | .04 |
| Uninsured | 573 | 6.5 (4.3-8.8) | 26,774 | 12.5 (11.8-13.1) | 0.52 (0.37-0.73) | .0009 | 0.44 (0.31-0.63) | <.0001 |
| Weekend admission | ||||||||
| No | 6440 | 73.2 (70.7-75.6) | 150,389 | 69.9 (69.4-70.3) | 1.00 (reference) | — | 1.00 (reference) | — |
| Yes | 2361 | 26.8 (24.4-29.3) | 64,843 | 30.1 (29.7-30.6) | 0.85 (0.75-0.97) | .04 | 0.85 (0.74-0.97) | .05 |
| Hospital location | ||||||||
| Metropolitan | 7331 | 83.3 (76.4-90.2) | 174,774 | 81.2 (79.9-82.5) | 1.00 (reference) | — | † | † |
| Not metropolitan Region | 1470 | 16.7 (9.8-23.6) | 40,459 | 18.8 (17.5-20.1) | 0.87 (0.53-1.42) | .69 | † | † |
| Northeast | 1758 | 20.0 (7.5-32.5) | 33,728 | 15.7 (14.1-17.2) | 1.00 (reference) | — | † | † |
| Midwest | 2302 | 26.2 (17.1-35.2) | 51,783 | 24.1 (22.1-26.0) | 0.85 (0.37-1.94) | .75 | † | † |
| South | 2396 | 27.2 (19.1-35.4) | 89,246 | 41.5 (39.2-43.7) | 0.52 (0.24-1.13) | .19 | † | † |
| West | 2345 | 26.6 (13.8-39.5) | 40,476 | 18.8 (17.1-20.5) | 1.11 (0.43-2.86) | .87 | † | † |
| Hospital teaching status | ||||||||
| Nonteaching | 4013 | 45.6 (33.8-57.3) | 103,334 | 48.0 (45.8-50.2) | 1.00 (reference) | — | † | † |
| Teaching | 4788 | 54.4 (42.7-66.2) | 111,899 | 52.0 (49.8-54.2) | 1.10 (0.69-1.76) | .75 | † | † |
| Season | ||||||||
| Winter | 1933 | 22.9 (20.0-25.8) | 45,400 | 22.5 (22.1-22.9) | 1.07 (0.88-1.30) | .68 | † | † |
| Spring | 2035 | 24.1 (21.1-27.1) | 51,198 | 25.4 (24.9-25.8) | 1.00 (reference) | — | † | † |
| Summer | 2418 | 28.6 (26.0-31.3) | 56,984 | 28.2 (27.8-28.7) | 1.07 (0.91-1.26) | .65 | † | † |
| Autumn | 2055 | 24.3 (20.4-28.2) | 48,233 | 23.9 (23.4-24.4) | 1.07 (0.83-1.38) | .69 | † | † |
Bold text indicates that the P value was statistically significant.
Multivariable model was adjusted for age, insurance status, weekend admission, and season after stepwise variable selection.
The variable was not included in the final multivariable models.
Among persons with HAE, the most common reasons for ED visit were HAE (prevalence [95% CI]: 79.3% [74.9-83.7%]) and abdominal pain (7.2% [4.9-9.6%]) (see Table E2 in this article’s Online Repository at www.jaci-inpractice.org). In adjusted logistic regression models, patients with HAE diagnosis had higher utilization of abdominal CT (adjusted OR [95% CI]: 9.32 [6.26-13.86]) and/or x-ray imaging (12.89 [7.20-23.09]) compared to patients with angioedema, and similar rates of chest x-rays (1.09 [0.79-1.51]) and intubation (1.10 [0.31-3.89]) (Table II). Even after adjusting for greater prevalence of abdominal symptoms, patients with HAE still had higher abdominal CT (6.32 [3.89-10.28]) and x-ray (9.35 [4.61-18.97]) utilization. Few patients with HAE had indication for abdominal CT imaging (Table III). Moreover, patients with HAE versus patients with angioedema had similar rates of conditions requiring abdominal CT imaging: pancreatitis, diverticulosis/diverticulitis, intussusception, and nephrolithiasis.
TABLE E2.
Reason for ED visit among patients with HAE and controls
| HAE diagnosis (n = 1917) | Angioedema diagnosis (n = 46,968) | No HAE/angioedema diagnosis (n = 56,217,496) | |||
|---|---|---|---|---|---|
| CCS diagnosis | % of visits (95% CI) Weighted frequency | CCS diagnosis | % of visits (95% CI) Weighted frequency | CCS diagnosis | % of visits (95% CI) Weighted frequency |
| Hereditary angioedema | 79.3% (74.9%-83.7%) 7073 | Angioedema | 95.1% (94.7%-95.5%) 204,838 | Upper respiratory tract infection | 4.7% (4.5%-4.9%) 12,094,298 |
| Abdominal pain | 7.2% (4.9%-9.6%) 646 | Allergic reactions | 1.8% (1.6%-2.0%) 3,796 | Abdominal pain | 4.6% (4.5%-4.7%) 11,729,042 |
| Angioedema | 1.1% (0.6%-1.7%) 101 | Poisoning not by prescribed medicine | 0.4% (0.4%-0.5%) 916 | Sprains and strains | 4.2% (4.1%-4.3%) 10,683,489 |
| Acute/chronic pain | 0.9% (0.0%-1.8%) 85 | Miscellaneous | 0.3% (0.2%-0.4%) 707 | Superficial contusion | 4.1% (4.1%-4.2%) 10,594,629 |
| Nausea and vomiting | 0.8% (0.4%-1.3%) 72 | Chest pain | 0.2% (0.1%-0.2%) 346 | Chest pain | 3.8% (3.7%-3.8%) 9,622,190 |
AHRQ, Agency for Healthcare Research and Quality; CCS, Clinical Classification Software.
CCS diagnosis indicates the diagnosis grouping based on the AHRQ Clinical Classification Software grouping schema.
TABLE II.
Imaging during ED visits with HAE vs angioedema
| Imaging | HAE diagnosis | Angioedema diagnosis | ||
|---|---|---|---|---|
| % of visits (95% CI) Weighted frequency | % of visits (95% CI) Weighted frequency | Adjusted OR* (95% CI) | P value | |
| Abdominal CT | 2.7% (1.8%-3.6%) 237 | 0.3% (0.3%-0.4%) 699 | 9.32 (6.26-13.86) | <.0001 |
| Noncontrast CT | 1.1% (0.5%-1.6%) 92 | 0.1% (0.1%-0.2%) 304 | 8.62 (4.81-15.42) | <.0001 |
| Contrast CT | 1.7% (1.0%-2.3%) 149 | 0.2% (0.1%-0.2%) 395 | 9.90 (6.04-16.24) | <.0001 |
| Abdominal x-ray | 1.7% (0.9%-2.4%) 146 | 0.1% (0.1%-0.2%) 261 | 13.26 (7.43-23.67) | <.0001 |
| Intubation | 0.2% (0.0%-0.4%) 15 | 0.2% (0.1%-0.2%) 414 | 1.10 (0.31-3.89) | .90 |
| Chest x-ray | 5.8% (4.3%-7.2%) 507 | 6.5% (6.1%-6.9%) 13,960 | 1.09 (0.79-1.51) | .69 |
Wtd Freq, weighted frequency; OR, odds ratio
Bold text indicates that the P value was statistically significant. Regression models were not constructed for cells with 0 cases.
Adjusted models adjusted for age (continuous), sex, and insurance payer.
TABLE III.
Imaging indications during ED visits with HAE vs angioedema
| Diagnosis | HAE diagnosis | Angioedema diagnosis | ||
|---|---|---|---|---|
| % of visits (95% CI) Weighted frequency | % of visits (95% CI) Weighted frequency | Adjusted OR* (95% CI) | P value | |
| Pancreatitis | 0.1% (0.0%-0.2%) ≤10† | 0.1% (0.1%-0.1%) 164 | 1.38 (0.33-5.79) | .75 |
| Diverticulosis/diverticulitis | 0.4% (0.0%-0.9%) 38 | 0.2% (0.1%-0.2%) 395 | 5.02 (1.33-18.90) | .05 |
| Cholecystitis | 0.0% (0.0%-0.0%) | 0.01% (0.0%-0.02%) ≤10 | — | — |
| Appendicitis | 0.0% (0.0%-0.0%) | 0.01% (0.0%-0.02%) 19 | — | — |
| Intussusception | 0.05% (0.0%-0.3%) ≤10† | 0.0% (0.0%-0.0%) | — | — |
| Nephrolithiasis | 0.2% (0.0%-0.3%) 14 | 0.1% (0.1%-0.1%) 182 | 2.47 (0.72-8.49) | .27 |
| Constipation | 1.3% (0.7%-2.0%) 119 | 0.3% (0.2%-0.3%) 619 | 6.08 (3.38-10.95) | <.0001 |
Bold text indicates that the P value was statistically significant. Regression models were not constructed for cells with 0 cases.
Adjusted models adjusted for age (continuous), sex, and insurance payer.
Values ≤10 are bottom-coded to preserve anonymity.
Among ED patients with HAE, 82.5% (95% CI, 77.5%-87.5%) were routinely treated and released and 8.2% (95% CI, 5.7%-10.7%) were hospitalized. Inpatient admission was higher in females (multivariable stepwise logistic regression: adjusted OR [95% CI], 2.34 [1.17-4.67]), adults aged 40 to 59 years (7.24 [2.84-18.45]), and individuals without health insurance (3.16 [1.45-6.90]) (see Table E3 in this article’s Online Repository at www.jaci-inpractice.org).
TABLE E3.
Sociodemographic and clinical associations of inpatient admission among patients with HAE
| Variable | Not admitted | Inpatient admission | ||||||
|---|---|---|---|---|---|---|---|---|
| Weighted frequency | Prevalence (95% CI) | Weighted frequency | Prevalence (95% CI) | Crude OR (95% CI) | P | Adjusted OR* (95% CI) | P | |
| Sex | ||||||||
| Male | 3019 | 93.7 (91.2-96.2) | 204 | 6.3 (3.8-8.8) | 1.00 (reference) | — | 1.00 (reference) | — |
| Female | 5181 | 90.9 (87.5-94.3) | 519 | 9.1 (5.7-12.5) | 1.48 (0.87-2.54) | .27 | 2.34 (1.17-4.67) | .04 |
| Age (y) | ||||||||
| <18 | 1594 | 97.8 (96.1-99.5) | 36 | 2.2 (0.5-3.9) | 1.00 (reference) | — | 1.00 (reference) | — |
| 18-39 | 2976 | 91.4 (88.5-94.3) | 282 | 8.6 (5.7-11.5) | 4.23 (1.69-10.58) | .008 | 3.13 (1.13-8.70) | .07 |
| 40-59 | 2153 | 86.9 (81.1-92.8) | 324 | 13.1 (7.2-18.9) | 6.72 (2.76-16.37) | .0002 | 7.24 (2.84-18.45) | .0002 |
| 60+ | 1477 | 94.7 (89.5-99.9) | 83 | 5.3 (0.1-10.5) | 2.50 (0.73-8.65) | .27 | 1.16 (0.22-6.00) | .89 |
| Income | ||||||||
| <50th %’ile | 4166 | 91.0 (88.2-93.9) | 410 | 9.0 (6.1-11.8) | 1.37 (0.72-2.60) | .52 | † | † |
| >50th %’ile | 3915 | 93.3 (89.8-96.8) | 281 | 6.7 (3.2-10.2) | 1.00 (reference) | — | † | † |
| Insurance status | ||||||||
| Private | 3100 | 93.3 (90.9-95.8) | 221 | 6.7 (4.2-9.1) | 1.00 (reference) | — | 1.00 (reference) | — |
| Public | 4606 | 91.9 (88.2-95.6) | 406 | 8.1 (4.4-11.8) | 1.24 (0.69-2.23) | .007 | 1.58 (0.92-2.72) | .19 |
| Uninsured | 490 | 83.5 (76.2-90.8) | 92 | 16.5 (9.2-23.8) | 2.78 (1.47-5.25) | .68 | 3.16 (1.45-6.90) | .01 |
| Weekend admission | ||||||||
| No | 6025 | 92.1 (89.6-94.6) | 517 | 7.9 (5.4-10.4) | 1.00 (reference) | — | † | † |
| Yes | 2175 | 91.3 (88.0-94.7) | 206 | 8.7 (5.3-12.0) | 1.11 (0.79-1.56) | .69 | † | † |
| Hospital location | ||||||||
| Metropolitan | 6761 | 91.0 (87.9-94.0) | 672 | 9.0 (6.0-12.1) | 1.00 (reference) | — | 1.00 (reference) | — |
| Not metropolitan | 1440 | 96.5 (93.3-99.8) | 52 | 3.5 (0.2-6.7) | 0.36 (0.13-1.02) | .11 | 0.35 (0.13-0.95) | .09 |
| Region | ||||||||
| Northeast | 1614 | 90.8 (83.2-98.5) | 163 | 9.2 (1.5-16.8) | 1.00 (reference) | — | 1.00 (reference) | — |
| Midwest | 2149 | 92.4 (88.1-96.8) | 176 | 7.6 (3.2-11.9) | 0.81 (0.27-2.44) | .75 | 0.58 (0.22-1.49) | .42 |
| South | 2165 | 88.3 (84.1-92.4) | 287 | 11.7 (7.6-15.9) | 1.31 (0.48-3.57) | .69 | 0.79 (0.34-1.82) | .69 |
| West | 2272 | 95.9 (92.8-99.0) | 98 | 4.1 (1.0-7.2) | 0.42 (0.13-1.41) | .28 | 0.33 (0.12-0.96) | .09 |
| Hospital teaching status | ||||||||
| Nonteaching | 3785 | 93.2 (90.7-95.7) | 275 | 6.8 (4.3-9.3) | 1.00 (reference) | — | † | † |
| Teaching | 4415 | 90.8 (86.5-95.1) | 448 | 9.2 (4.9-13.5) | 1.40 (0.73-2.68) | .50 | † | † |
| Season | ||||||||
| Winter | 1820 | 91.9 (88.4-95.4) | 160 | 8.1 (4.6-11.6) | 1.15 (0.71-1.86) | .69 | † | † |
| Spring | 1909 | 92.8 (89.8-95.9) | 147 | 7.2 (4.1-10.2) | 1.00 (reference) | — | † | † |
| Summer | 2309 | 93.6 (91.0-96.3) | 157 | 6.4 (3.7-9.0) | 0.88 (0.54-1.43) | .69 | † | † |
| Autumn | 1885 | 91.4 (87.8-95.0) | 178 | 8.6 (5.0-12.2) | 1.22 (0.72-2.07) | .67 | † | † |
Bold text indicates that the P value was statistically significant.
Multivariable model was adjusted for sex, age, insurance status, hospital location, and region after stepwise variable selection.
The variable was not included in the final multivariable models.
During the period 2015 to 2016, the mean total annual ED cost of care was $32,939,152 for patients with HAE, compared to $288,673,186 for patients with angioedema. Visits of patients with HAE versus angioedema had higher mean costs per visit ($3598 vs $1893) in bivariable (b [95% CI]: 4.72 [2.97-7.49]; P < .0001) and multivariable linear regression models adjusted for age, sex, and insurance payer (6.06 [3.79-9.68]; P < .0001) (see Figure E1 in this article’s Online Repository at www.jaci-inpractice.org ).
FIGURE E1.
Geometric mean cost per visit for ED visits with HAE vs angioedema. Error bars denote standard error of the costs for ED visits. All refers to an ED visit for any reason.
This study found that despite the rarity of HAE and introduction of new targeted therapies, there remains a high health care and financial burden in the ED. Given the frequent use of emergency services compared with the only other study on this topic conducted more than 1 decade ago,4 this suggests that on-demand therapy is either not working adequately or not used frequently enough. There may be additional opportunities to improve access to on-demand, self-administered therapy and individualized support and management.6 Higher ED cost in patients with HAE versus patients with angioedema may be explained by difference in severity. Previously diagnosed patients with HAE may present to the ED only with extreme symptoms, whereas patients with angioedema but without HAE may never have had angioedema and present with mild symptoms.
Abdominal imaging in our cohort was frequently ordered. This finding aligns with published case studies that have reported that HAE-mediated abdominal pain presents similarly to and is often mistaken for appendicitis, bowel obstruction, or other gastrointestinal disease, leading to unnecessary imaging and even surgeries such as cholecystectomy and hysterectomy.3,7 Radiologic imaging is not indicated in patients with known HAE, unless there is concern for unrelated abdominal pathology (eg, appendicitis), or the rare complication of HAE, intussusception (prevalence of 0.05% in our study).8 A trial of targeted HAE therapy should be considered before embarking on extensive diagnostic testing and imaging to minimize unnecessary workup. Collaboration between emergency physicians, allergists, and radiologists may improve management of acute HAE episodes and promote radiology stewardship. A recent trial found that a national emergency call center was effective in reducing hospitalization.9
Strengths of this study include the large cohort size (>56 million ED visits over 2 years) and population-based sampling that allows for nationwide estimates. However, there are limitations. We analyzed a population sample of the United States; generalizability to other countries may depend on differences in access and care. Second, patients were identified using International Classification of Diseases codes as described by other studies4; however, International Classification of Diseases codes may not correlate exactly with HAE diagnosis. The difficulty to diagnose HAE, particularly in the emergency setting, is well documented. Thus, these data likely underestimate the prevalence of HAE-associated ED visits. Finally, data were unavailable on HAE severity, phenotypes, imaging findings, follow-up outpatient care, and treatment patterns. Additional studies are needed to determine strategies to minimize ED burden and decrease unnecessary abdominal imaging.
Clinical Implications.
There are high rates of unnecessary radiology during emergency department (ED) visits of patients with hereditary angioedema. Multidisciplinary collaboration is needed to decrease unnecessary imaging and promote radiology stewardship in the ED.
Footnotes
Conflicts of interest: The authors declare that they have no relevant conflicts of interest.
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