Original Article

Clinical Features of Pediatric Hereditary Angioedema Maya K. Nanda, MD, MSca, Shelby Elenburg, MDb, Jonathan A. Bernstein, MDc, and Amal H. Assa’ad, MDa Cincinnati, Ohio; and Memphis, Tenn

What is already known about this topic? Pediatric hereditary angioedema (HAE) is classically described as a disease with onset of symptoms in the teenage years; however, earlier onset of symptoms is often missed and contributes to a delay in diagnosis. What does this article add to our knowledge? This study shows an earlier age of symptom onset of 5.7 years and age of diagnosis of 5.0 years; children without a family history experienced a 6-year delay in diagnosis. How does this study impact current management guidelines? These findings emphasize the need to screen children suspected of having HAE at an earlier age and if positive then the need to develop an on-demand treatment plan for these children. BACKGROUND: There is a paucity of data that describe the clinical course of hereditary angioedema (HAE) in children. OBJECTIVE: The purpose of this study was to examine the clinical features of children with HAE. METHODS: Electronic medical records from the past 10 years at Cincinnati Children’s Hospital Medical Center and an outpatient allergy community practice were searched for ICD-9 code 277.6 (Other deficiencies of circulating enzyme). Exclusion criteria included laboratory data not supportive of type I or II HAE diagnosis or age at diagnosis greater than 18 years. Chart review was performed and missing data were collected by telephone interviews with patient families. Descriptive statistics were performed using SAS version 9.4. a

Division of Allergy, Asthma, and Immunology, Children’s Mercy Hospital, Kansas City, Mo. Formerly and work performed at Division of Allergy & Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio b Division of Allergy and Immunology, University of Tennessee Health Science Center, Memphis, Tenn c Division of Immunology, University of Cincinnati, Cincinnati, Ohio The study was funded by National Institutes of Health/National Institute of Allergy and Infectious Diseases grant T32 AI060515. Conflicts of interest: M. K. Nanda has received research support from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (grant T32 AI060515). S. Elenburg declares no relevant conflicts. J. A. Bernstein is on the US Hereditary Angioedema Association Medical Advisory Board and the American Academy of Allergy, Asthma, & Immunology Board of Directors; has received consultancy fees from CSL Behring, Shire/ViroPharma, Dyax, and Pharming; and has received research support and lecture fees from CSL Behring, Shire/ViroPharma, and Dyax. A. H. Assa’ad is on the American Academy of Allergy, Asthma, & Immunolog Board; is employed by Cincinnati Children’s Hospital; has received research support from DVB Technologies, Allergen Research Corporation, GlaxoSmithKline (MEA115661, MEA115588, MEA115575), and Cephalon (C38072/3084); and has received lecture fees from the Toledo Pediatric Society, Genessee Pediatric Society, and California Allergy Society. Received for publication August 7, 2014; revised November 18, 2014; accepted for publication November 19, 2014. Available online -Corresponding author: Maya K. Nanda, MD, MSc, Division of Allergy, Asthma, and Immunology, Children’s Mercy Hospital, 2401 Gillham Rd, Kansas City, Mo 64108. E-mail: [email protected] 2213-2198 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2014.11.012

RESULTS: Twenty-one children were identified. The median age was 13.2 years (interquartile range [IQR], 9.1-18.8), 71% were male, 86% had an HAE family history, and 95% were Caucasian. The median age of symptom onset and diagnosis was 5.7 (IQR, 5-9 years) and 5.0 (IQR, 4-8 years), respectively. Five children diagnosed were asymptomatic. Three children without a family history had a 6.0-year delay in diagnosis. The most common angioedema attack sites were abdominal, peripheral, and laryngeal, which occurred at least once in 93%, 73%, and 27%, respectively. Of the 15 children with onset of symptoms, only 6 children received on-demand therapy for an acute attack, whereas 13 children were administered either short-term or long-term prophylaxis therapy. CONCLUSIONS: In this pediatric HAE population, symptom onset and diagnosis occurred at a median age of 5 years with a delay in diagnosis in those without a family history. Abdominal attacks were more common than peripheral attacks in this population. Ó 2015 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2015;-:---) Key words: Pediatric hereditary angioedema; Hereditary angioedema; Age onset

Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by episodic nonpitting edema of the face, neck, abdomen, extremities, and genitals.1,2 Mutations in the C1 inhibitor (C1-INH) gene, SERPING1, lead to bradykinin overproduction and swelling attacks.3,4 Although the defect is present at birth, presentation of clinical disease was initially reported to occur during the second decade of life. Bork et al reported in 209 HAE patients that the mean age of symptom onset was 11.2 years.5 Another large study of 444 Spanish HAE patients reported a mean age of symptom onset of 12.6 years.6 Although HAE is classically described as a disease with onset of symptoms in the teenage years, reports of symptoms in first decade of life are not uncommon.7 The failure to recognize onset of symptoms early in life can lead to a significant delay in diagnosis. Survey studies have reported that the average delay in diagnosis is between 11 and 20 years.6,7 Factors 1

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Abbreviations used C1-INH- C1 inhibitor CCHMC- Cincinnati Children’s Hospital Medical Center EMR- Electronic medical records ER- Emergency room HAE- Hereditary angioedema IQR- Interquartile range pdC1INH- Plasma-derived C1 inhibitor

that lead to a delay in diagnosis include lack of recognition of symptoms, misdiagnosis, and absence of a family history as de novo mutations have been estimated to occur in up to 25% of patients.8 There are few treatment options for children with HAE,9,10 and in many cases parents often decide, possibly based on their personal experiences with the disease as a child, against having their child evaluated by a physician. This has also resulted in the paucity of epidemiologic information on this population. Studies have found that the most common site of swelling episodes in adult and pediatric HAE populations was the peripheral extremities11 followed closely by abdominal attacks and that an earlier age of disease onset was associated with more frequent attacks.5,7 Although the location of swelling episodes have been well characterized in adults, less is known about the clinical presentation of HAE in children. Thus, we sought to better define the age and initial presenting symptoms in a pediatric HAE population under 18 years of age.

METHODS Electronic medical records (EMR) from the past 10 years at Cincinnati Children’s Hospital Medical Center (CCHMC) and paper charts from a community allergy practice were searched for the diagnosis of HAE defined as ICD-9 code 277.6 (Other deficiencies of circulating enzyme). Children with this diagnosis code were excluded if laboratory data did not support diagnosis of type I or II HAE or if the age was greater than 18 years at the time of physician diagnosis. Data was collected uniformly for each patient using a template which included the current age of the patient, gender, ethnicity, age at diagnosis, age at symptom onset, associated diseases, triggers for attacks, laboratory results (C1-INH, C1 inhibitor function, C1q, C2, C3, C4), treatment modalities for acute attacks after diagnosis, number of emergency room (ER) visits after diagnosis, number of hospitalizations and average number of days hospitalized, current medications, number of lifetime laryngeal attacks if applicable, and average number of attacks per year since diagnosis (divided into abdominal, peripheral, and laryngeal attacks). Children with missing information by the chart review were contacted by telephone for interview using a telephone script. If the child was under the age of 16 years, the parent was interviewed. If the child was 16 years or older, both the parent and child were interviewed. SAS 9.4 (SAS Institute, Cary, North Carolina) was used to perform descriptive analysis and to test the association of age of symptom onset and age of diagnosis with attack frequency, severity, and location using c2 and Fisher’s exact tests. The survivor function using the proc lifetest was used to calculate the median age of symptom onset. This analysis was used because of the ability to censor observations of children who were asymptomatic at the time of analysis. All parents of children (or the child if older than 18 years) provided verbal informed consent or assent, and the Institutional Review Board at CCHMC approved this study with a waiver of written consent.

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TABLE I. Demographic characteristics of the 21 children with hereditary angioedema n (%)

Gender Male Female Ethnicity White Other Family history of HAE Present Absent Comorbid diseases None Atopy Frequent infection Asthma Migraines C1 inhibitor Level (mg/dL)

15 (71) 6 (29) 20 (95) 1 (5) 18 (86) 3 (14) 13 (65) 3 (15) 2 (10) 1 (5) 1 (5) Median (IQR) 6.0 (4.75-8.75)

HAE, hereditary angioedema; IQR, interquartile range.

RESULTS There were 21 children with a diagnosis of type I or II HAE included in this study who were fairly evenly distributed between the 2 sites. One child had data limited to gender, ethnicity, family history, age at diagnosis, and laboratory tests. Of these 21 children, 15 (71%) were male, 20 (95%) were Caucasian, and 18 (86%) had a family history of HAE (Table I). At the time of the final phone interview in September 2013, the current median age was 13.2 years (interquartile range [IQR], 9.1-18.8). The median age of symptom onset was 5.7 years (IQR, 5-9 years) in 21 children; using the survivor function analysis, 5 children without symptoms were censored observations and 1 was missing this information (Figure 1, Table II). The majority of these children had symptom onset in the first decade of life (n ¼ 13 of the 15 children with symptom onset). One of the 2 children identified with symptom onset in the second decade of life had no family history of HAE. The median age of diagnosis was 5.0 years (IQR, 4-8 years) in all 21 children, which was 0.7 years before the age of symptom onset (Table II). The majority of these children had a family history (n ¼ 18); these children had a diagnosis made 0.9 years before symptom onset, whereas children without a family history (n ¼ 3) had a median delay in diagnosis of 6.0 years (Table II). Age of symptom onset (greater than 5 years) or age of diagnosis (greater than 5 years) was not significantly associated with family history, ER visits, hospitalizations, more frequent (greater than 6 per year) attacks, and peripheral (yes/no) or laryngeal attacks (yes/no). Age of symptom onset greater than 5 years was significantly associated with having abdominal attacks (P ¼ .04). Stress was the most commonly reported trigger for attacks, which was reported by 9 children (60%) (Table III). The mean numbers of lifetime hospitalizations and ER visits per year were 0.8 (0-6) and 1.4 (0-12), respectively, in 19 children; information was missing for 2 children. Most children (65%) reported no other underlying medical history. The most commonly reported concomitant disease was atopy (including eczema and/or allergic rhinitis) in 15% of children followed by self-reported

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FIGURE 1. Age at symptom onset and age at diagnosis for each of 20 children with hereditary angioedema. One patient excluded who reported age at diagnosis of 2 years, but did not report age at symptom onset. + indicates that the patient has been diagnosed, but has yet to have onset of symptoms. *Each set of bars represents an individual patient.

TABLE II. Ages at diagnosis and symptom onset in 21 children with hereditary angioedema (HAE) Age at diagnosis (n ¼ 21) Mean (range) 6.3 (1-16) Median (IQR) 5.0 (4-8) Age at symptom onset (n ¼ 21)* Mean (range) 6.5 (2-12) Median (IQR) 5.7 (5-9) Age at diagnosis Family history (n ¼ 18)†, median (IQR) 5.0 (2.0-7.5) No family history (n ¼ 3)z, median (IQR) 10.0 (5-16) Age at symptom onset Family history (n ¼ 12)x, median (IQR) 5.9 (5.0-8.5) No family history (n ¼ 3/21)z, median (IQR) 4.0 (4-10) IQR, interquartile range. *All 21 children were entered into the survival function analysis and those without onset of symptoms were censored observation. †18 patients who reported a family history of HAE were used in this analysis. z3 patients who did not report a family history of HAE were used in this analysis. x12 patients who reported a family history and onset of symptoms were used in this analysis.

recurrent sinopulmonary infections in 10% of children (Table I). The median C1-INH level was 6.0 mg/dL (IQR, 4.75-7.85); reference range 21-39 mg/dL. Complete data sets were not available for C4 and C1-INH functional levels. The most common attacks were abdominal episodes, which occurred at least once in lifetime in 14 of 15 children (93%). Eleven of the 15 patients with symptom onset who were interviewed by telephone had a parent and/or child report severe pain and ER visit with the first 1 or 2 episodes of abdominal pain and then cited a frequency of attacks similar to these. Although no objective data were collected to verify these attacks, the historical accounts given by these families were consistent with HAE abdominal symptoms, course, and treatment. Peripheral attacks were reported by 11 children (73%) and laryngeal attacks by 4 children (Table III). Laryngeal attacks occurred once in a lifetime

TABLE III. Characteristics of disease in 15 children with hereditary angioedema who reported onset of symptoms Triggers for attacks n (%) Stress 9 (60) Trauma 7 (47) Infection 7 (47) Repetitive vibratory stimuli 4 (27) Weather 3 (20) Emotional upset 2 (13) Lack of sleep 2 (13) Types of attacks n (%) Abdominal 14 (93) Peripheral 11 (73) Laryngeal 4 (27) Number of attacks per year Median (IQR) Peripheral 4.0 (0-6.0) Abdominal 2.0 (0.25-6.0) Laryngeal 0 (0-1.0) Severity of attacks Mean (range) Hospitalizations in lifetime 0.8 (0-6) Emergency room visits per year 1.4 (0-12) IQR, interquartile range.

in 2 children and twice in a lifetime in 2 children. The median number of abdominal attacks per year was 2.0 (IQR, 0.25-6.0) and the median number of peripheral attacks per year was 4.0 (0-6.0) in the 15 children reporting symptom onset (Table III). More children reported ever having an abdominal attack; however, peripheral attacks had a higher frequency of attacks per year. The overall median number of attacks per year was 5.5 (2.0-12.0). In the 15 children with active HAE symptoms, 9 reported no treatment for acute attacks, 5 reported use of intravenous nanofiltered, plasma-derived C1 inhibitor (pdC1INH) for acute attacks, and 1 reported anabolic steroid use for acute attacks. For short-term prophylaxis, 10 children reported intravenous pdC1INH preprocedural and/or rescue treatment. For long-term prophylaxis, 1 child

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reported weekly pdC1INH use and 2 children reported daily anabolic steroid use. One adverse reaction reported in the EMR was precocious puberty in a 5-year-old boy started on anabolic steroids; further information from this family could not be obtained by telephone and family resided in another major city in Ohio.

DISCUSSION The median age of symptom onset of HAE attacks in our study was 5.7 years, which is consistent with prior findings; however, the mean age of symptom onset often cited in practice and the literature is still 11.2 years.5 Our results reflect the findings by Farkas et al, who reported an earlier onset of symptoms with a mean age of 6.6 years,7 and Agostoni et al, who reported that 50% of their patients had symptom onset in the first decade of life.12 Interestingly, we found a larger percentage of children experienced symptom onset in the first decade of life (87%), which could possibly be explained by limiting this analysis to children less than 18 years of age and excluding our adult HAE population.12 However, this potential bias is less relevant given that our population was predominantly identified and diagnosed based on family history and not clinical symptoms. One of the first studies published on HAE reported that 18 of 38 patients (47%) had onset of symptoms by age 6 years.13 Despite these prior studies, the current belief is still that HAE onset is in the second decade of life and therefore perpetuates the delay in diagnosis. As of 2005, the average delay in diagnosis is still 10 years, and this study also found a delay in diagnosis of 6 years in those children without a family history of HAE.14 Abdominal attacks were more common than peripheral attacks in this study, which is consistent with some prior surveys5,10,12; however, other studies have reported peripheral attacks as being more common.7 As both locations are very prevalent in HAE patients, whether the abdomen or extremities are the most frequent location could easily vary depending on the cross-sectional populations being analyzed. It is also possible that families recall abdominal attacks more often compared with minor peripheral extremity swelling episodes as they are more painful for the child and warrant medical intervention. Thus, the frequency of attacks reported is subject to recall bias because objective data were not collected to verify each attack as an HAE episode. Prior studies have suggested that the acute attacks in childhood are milder13; however, Farkas et al demonstrated that 54% of pediatric patients required emergency intervention before adulthood.15 Because abdominal pain is a common pediatric complaint in a child without HAE and any family history, it is important to first exclude other more common clinical conditions such as acute appendicitis, intussusception, Meckel’s diverticulum, and ovarian torsion. If there is high suspicion for HAE in a younger child presenting with repeated bouts of abdominal pain, a screening C4 should be obtained followed by a C1-INH functional and quantitative level if it is low. There are some limitations to this study, which include recall bias, interviewer bias, and small sample size. We attempted to reduce these biases by using uniform templates and telephone scripts to collect data from the patient’s chart review, electronic medical record, and telephone interview. To increase the sample size, we recruited from a large tertiary children’s hospital and a busy outpatient private practice, which specializes in angioedema. Another limitation of this study is the lack of objective diagnosis of HAE abdominal attacks (eg, CT scan or ultrasound

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of the abdomen to assess for bowel wall edema). Information on abdominal attacks was collected from charts and phone interviews; thus, the report of abdominal pain as an HAE attack was based on the parent’s experience with the disease. The strengths of this study include a study population of only children with HAE and clinically relevant historical data that were verified by telephone with the majority of families. In summary, this study provides important additional clinical data pertaining to children with HAE. Our data suggest that symptoms of HAE start in early childhood. The age of onset of HAE had been reported to be in early childhood7 and late childhood.5 These discrepancies are likely related to the same sample size and differences across populations. However, this study adds evidence that onset of symptoms often occurs in the first decade of life. It also emphasizes the need to establish a diagnosis of HAE in children early on to improve their quality of life and clinical outcomes. Future clinical trials should be encouraged for obtaining pediatric approval of novel HAE therapies that based on our findings should be designed to include children at least 2 years of age and older.

Acknowledgments We would like to thank Jane Khoury, PhD, for her guidance in data analysis and Shawna Hottinger, MS, for her edits to the tables and figure. We would also like to thank Purvin Lapsiwala, MBA, for his endless support. REFERENCES 1. Zuraw BL, Bernstein JA, Lang DM, Craig T, Dreyfus D, Hsieh F, et al. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol 2013;131:1491-3. 2. Osler W. Hereditary angio-neurotic oedema. Am J Med Sci 1888;95:362-7. 3. Donaldson VH, Evans RR. A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C’1-esterase. Am J Med 1963;35: 37-44. 4. Pappalardo E, Caccia S, Suffritti C, Tordai A, Zingale LC, Cicardi M. Mutation screening of C1 inhibitor gene in 108 unrelated families with hereditary angioedema: functional and structural correlates. Mol Immunol 2008;45: 3536-44. 5. Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med 2006;119: 267-74. 6. Roche O, Blanch A, Caballero T, Sastre N, Callejo D, López-Trascasa M. Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain. Ann Allergy Asthma Immunol 2005;94: 498-503. 7. Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma Clin Immunol 2010;6:18. 8. Pappalardo E, Cicardi M, Duponchel C, Carugati A, Choquet S, Agostoni A, et al. Frequent de novo mutations and exon deletions in the C1 inhibitor gene of patients with angioedema. J Allergy Clin Immunol 2000;106:1147-54. 9. Boyle RJ, Nikpour M, Tang ML. Hereditary angio-oedema in children: a management guideline. Pediatr Allergy Immunol 2005;16:288-94. 10. Schneider L, Hurewitz D, Wasserman R, Obtulowicz K, Machnig T, Moldovan D, et al. C1-INH concentrate for treatment of acute hereditary angioedema: a pediatric cohort from the I.M.P.A.C.T. studies. Pediatr Allergy Immunol 2013;24:54-60. 11. Abinun M. Hereditary angio-oedema in children. Lancet 1999;353:2242. 12. Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore) 1992; 71:206-15. 13. Donaldson VH, Rosen FS. Hereditary angioneurotic edema: a clinical survey. Pediatrics 1966;37:1017-27. 14. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med 2008;359: 1027-36. 15. Farkas H, Csuka D, Zotter Z, Szabó E, Czaller I, Varga L, et al. Treatment of attacks with plasma-derived C1-inhibitor concentrate in pediatric hereditary angioedema patients. J Allergy Clin Immunol 2013;131:909-11.

Clinical features of pediatric hereditary angioedema.

There is a paucity of data that describe the clinical course of hereditary angioedema (HAE) in children...
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