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Mimics of Angioedema
Abstracts AB247
J ALLERGY CLIN IMMUNOL VOLUME 137, NUMBER 2
Mimics of Angioedema
Jacqueline Hirsh1, Christina C. Price, MD2; 1Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT. RATIONALE: Allergy & Immunology specialists are often consulted for the clinical question, ‘‘Does this patient have angioedema?’’ Our goal was to identify mimics of angioedema, which should be considered when confronted with a patient who presents with possible angioedema. METHODS: Cases of presumed angioedema in a large, urban teaching hospital were reviewed. Atypical clinical and laboratory features were identified. RESULTS: Two patients with presentations concerning for angioedema but unrevealing work-ups were identified. Patient 1, a 49-year-old man, presented in 2013 with laryngeal and epiglottal edema in the absence of urticaria or tongue swelling, but with airway compromise requiring intubation. He had several similar subsequent presentations. C1 esterase and C4 levels were normal. He was ultimately found to have SVC syndrome with subclavian stenosis, which is the likely etiology of his presentation. Patient 2, a 65-year-old man, presented in 2014 with dysarthric speech and tongue swelling. He, too, had normal C1 esterase and C4 levels. He was ultimately diagnosed with myasthenia gravis to which his angioedema-like picture was attributed. Both of these patients’ angioedema-like presentations were initially attributed to ACE-inhibitor exposure, but they were subsequently found to have more plausible etiologies mimicking angioedema. CONCLUSIONS: Although angioedema is a common diagnosis made by Allergy & Immunology specialists, many mimics exist. When hereditary angioedema is ruled out, as it was in our two patients, the question of secondary etiology versus angioedema-mimic arises. In the two patients reviewed, ACE-inhibitor-induced angioedema was the initial diagnosis until their clinical syndromes revealed themselves as mimics of angioedema. 2
806
Assessment of Inhibitory Antibody Formation in Subjects with Hereditary Angioedema Treated with Plasma-Derived C1-Esterase Inhibitor Concentrate (BerinertÒ)
Henriette Farkas, MD, PhD, DSc1, Dumitru Moldovan, MD, PhD2, Krystyna Obtu A, owicz, MD3, T. Shirov, MD, PhD4, Jonathan M. 5 Edelman, MD , Debora Williams-Herman, MD5, Mikhail Rojavin, PhD5; 1Semmelweis University, Budapest, Hungary, 2Department of Allergology–Immunology, Mures County Hospital, Tirgu-Mures, Romania, 3Jagiellonian University, Krakow, Poland, 4MHAT ‘‘Tsaritsa Yoanna - ISUL’’, Sofia, Bulgaria, 5CSL Behring, King of Prussia, PA. RATIONALE: Limited data are available regarding C1-esterase inhibitor (C1-INH) administration and anti-C1-INH antibodies. This study assessed the incidence and relevance of antibody formation during treatment with pasteurized, nanofiltered plasma-derived C1-INH (pnfC1-INH; BerinertÒ/ CSL Behring) in subjects with hereditary angioedema with C1-INH deficiency (C1-INH-HAE). METHODS: In this multicenter, open-label study, subjects with C1-INH_ 12 years of age) were given pnfC1-INH 20 IU/kg per HAE attack HAE (> that required treatment and followed for 9 months. Blood samples were taken at baseline (day of first attack) and Months 3, 6, and 9 and analyzed for inhibitory (iC1-INHab) and non-inhibitory anti-C1-INH antibodies (niC1-INHab). RESULTS: The study included 46 subjects (69.6% female; mean age, 38.9 y; all Caucasian) who received 221 on-site pnfC1-INH infusions; _6 infusions. No subject tested positive (titer > _1:50) most subjects received < for iC1-INHab at any time during the study. Thirteen (28.2%) subjects _1 sample. Nine (19.6%) subjects had had detectable niC1-INHab in > detectable niC1-INHab at baseline; three of these had no detectable _1 detectable result antibodies post-baseline. Of 10 (21.7%) subjects with > for niC1-INHab post-baseline, 6 had detectable niC1-INHab at baseline.
Mean times to complete symptom resolution per subject and per attack were similar between the group of subjects who tested positive at any time for niC1-INHab and the group of subjects who consistently tested negative. CONCLUSIONS: Administration of pnfC1-INH was not associated with inhibitory anti-C1-INH antibody formation in this population. Non-inhibitory antibodies were detected in some patients but fluctuated during the study independently of pnfC1-INH administration and appeared to have no impact on pnfC1-INH efficacy.
807
Low Levels of Melatonin Increase Nitric Oxide Production from IFN-Gamma/Vitamin D Stimulated PBMC and May Contribute to Seasonal Increase in Angiodema in Summer
Karyn Winkler, MD1,2, Dylan Martin, BS3, Maja Nowakowski, PhD4, Rauno Joks, MD1,5; 1Center for Allergy and Asthma Research, 2 Department of Pediatrics, 3College of Medicine, 4Department of Pathology, 5Department of Medicine, SUNY Downstate Medical Center, Brooklyn, NY. RATIONALE: We have previously reported a seasonal increase in angioedema, but not urticaria, in the summer months, peaking in June. Melatonin, a factor responsible for sleep-wake cycles, is decreased during long summer days. As melatonin is known to suppress eNOS, which is upregulated by bradykinin, we hypothesized that decreased melatonin levels are associated with increased nitric oxide production from stimulated PBMC. METHODS: Blood was drawn from healthy subjects (n56) between 8 - 11 AM and PBMC (3x106/ml) were stimulated with bradykinin (100 nmol/mL), 6 hIL-15 (1 mg/mL), 6IL-18 (1 ug/mL) (Group1), recombinant human melatonin (1,10, 100 pmol/mL, M1, M2, M3, respectively), and IFN-gamma (10 ng/ml)/ Vitamin D3 (20 pmol/mL) (Group 2). Cells were incubated for 5 days, and nitric oxide levels determined using Griess reaction. RESULTS: Stimulation with Group 1 did not increase NO production above baseline (base: 0.6160.76 mM, Group 1: 0.6360.79 mM, p50.62). Addition of M1-M3 to Group 1 did not alter NO production (0.5960.72 mM, 0.6260.66 mM, 0.5960.76 mM) (p5ns). However, addition of Group 2 to Group1/M1-M3 treated PBMCs resulted in a significant increase in NO: (1.8460.21 mM 1.4860.42 mM, 1.0260.52 mM) (p<0.01, p50.046, p50.26, respectively). CONCLUSIONS: Prolonged, low daytime levels of melatonin increase nitric oxide production from Interferon-gamma stimulated leukocytes and may contribute to seasonal angioedema.
MONDAY
805
J ALLERGY CLIN IMMUNOL VOLUME 137, NUMBER 2
Mimics of Angioedema
Jacqueline Hirsh1, Christina C. Price, MD2; 1Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT. RATIONALE: Allergy & Immunology specialists are often consulted for the clinical question, ‘‘Does this patient have angioedema?’’ Our goal was to identify mimics of angioedema, which should be considered when confronted with a patient who presents with possible angioedema. METHODS: Cases of presumed angioedema in a large, urban teaching hospital were reviewed. Atypical clinical and laboratory features were identified. RESULTS: Two patients with presentations concerning for angioedema but unrevealing work-ups were identified. Patient 1, a 49-year-old man, presented in 2013 with laryngeal and epiglottal edema in the absence of urticaria or tongue swelling, but with airway compromise requiring intubation. He had several similar subsequent presentations. C1 esterase and C4 levels were normal. He was ultimately found to have SVC syndrome with subclavian stenosis, which is the likely etiology of his presentation. Patient 2, a 65-year-old man, presented in 2014 with dysarthric speech and tongue swelling. He, too, had normal C1 esterase and C4 levels. He was ultimately diagnosed with myasthenia gravis to which his angioedema-like picture was attributed. Both of these patients’ angioedema-like presentations were initially attributed to ACE-inhibitor exposure, but they were subsequently found to have more plausible etiologies mimicking angioedema. CONCLUSIONS: Although angioedema is a common diagnosis made by Allergy & Immunology specialists, many mimics exist. When hereditary angioedema is ruled out, as it was in our two patients, the question of secondary etiology versus angioedema-mimic arises. In the two patients reviewed, ACE-inhibitor-induced angioedema was the initial diagnosis until their clinical syndromes revealed themselves as mimics of angioedema. 2
806
Assessment of Inhibitory Antibody Formation in Subjects with Hereditary Angioedema Treated with Plasma-Derived C1-Esterase Inhibitor Concentrate (BerinertÒ)
Henriette Farkas, MD, PhD, DSc1, Dumitru Moldovan, MD, PhD2, Krystyna Obtu A, owicz, MD3, T. Shirov, MD, PhD4, Jonathan M. 5 Edelman, MD , Debora Williams-Herman, MD5, Mikhail Rojavin, PhD5; 1Semmelweis University, Budapest, Hungary, 2Department of Allergology–Immunology, Mures County Hospital, Tirgu-Mures, Romania, 3Jagiellonian University, Krakow, Poland, 4MHAT ‘‘Tsaritsa Yoanna - ISUL’’, Sofia, Bulgaria, 5CSL Behring, King of Prussia, PA. RATIONALE: Limited data are available regarding C1-esterase inhibitor (C1-INH) administration and anti-C1-INH antibodies. This study assessed the incidence and relevance of antibody formation during treatment with pasteurized, nanofiltered plasma-derived C1-INH (pnfC1-INH; BerinertÒ/ CSL Behring) in subjects with hereditary angioedema with C1-INH deficiency (C1-INH-HAE). METHODS: In this multicenter, open-label study, subjects with C1-INH_ 12 years of age) were given pnfC1-INH 20 IU/kg per HAE attack HAE (> that required treatment and followed for 9 months. Blood samples were taken at baseline (day of first attack) and Months 3, 6, and 9 and analyzed for inhibitory (iC1-INHab) and non-inhibitory anti-C1-INH antibodies (niC1-INHab). RESULTS: The study included 46 subjects (69.6% female; mean age, 38.9 y; all Caucasian) who received 221 on-site pnfC1-INH infusions; _6 infusions. No subject tested positive (titer > _1:50) most subjects received < for iC1-INHab at any time during the study. Thirteen (28.2%) subjects _1 sample. Nine (19.6%) subjects had had detectable niC1-INHab in > detectable niC1-INHab at baseline; three of these had no detectable _1 detectable result antibodies post-baseline. Of 10 (21.7%) subjects with > for niC1-INHab post-baseline, 6 had detectable niC1-INHab at baseline.
Mean times to complete symptom resolution per subject and per attack were similar between the group of subjects who tested positive at any time for niC1-INHab and the group of subjects who consistently tested negative. CONCLUSIONS: Administration of pnfC1-INH was not associated with inhibitory anti-C1-INH antibody formation in this population. Non-inhibitory antibodies were detected in some patients but fluctuated during the study independently of pnfC1-INH administration and appeared to have no impact on pnfC1-INH efficacy.
807
Low Levels of Melatonin Increase Nitric Oxide Production from IFN-Gamma/Vitamin D Stimulated PBMC and May Contribute to Seasonal Increase in Angiodema in Summer
Karyn Winkler, MD1,2, Dylan Martin, BS3, Maja Nowakowski, PhD4, Rauno Joks, MD1,5; 1Center for Allergy and Asthma Research, 2 Department of Pediatrics, 3College of Medicine, 4Department of Pathology, 5Department of Medicine, SUNY Downstate Medical Center, Brooklyn, NY. RATIONALE: We have previously reported a seasonal increase in angioedema, but not urticaria, in the summer months, peaking in June. Melatonin, a factor responsible for sleep-wake cycles, is decreased during long summer days. As melatonin is known to suppress eNOS, which is upregulated by bradykinin, we hypothesized that decreased melatonin levels are associated with increased nitric oxide production from stimulated PBMC. METHODS: Blood was drawn from healthy subjects (n56) between 8 - 11 AM and PBMC (3x106/ml) were stimulated with bradykinin (100 nmol/mL), 6 hIL-15 (1 mg/mL), 6IL-18 (1 ug/mL) (Group1), recombinant human melatonin (1,10, 100 pmol/mL, M1, M2, M3, respectively), and IFN-gamma (10 ng/ml)/ Vitamin D3 (20 pmol/mL) (Group 2). Cells were incubated for 5 days, and nitric oxide levels determined using Griess reaction. RESULTS: Stimulation with Group 1 did not increase NO production above baseline (base: 0.6160.76 mM, Group 1: 0.6360.79 mM, p50.62). Addition of M1-M3 to Group 1 did not alter NO production (0.5960.72 mM, 0.6260.66 mM, 0.5960.76 mM) (p5ns). However, addition of Group 2 to Group1/M1-M3 treated PBMCs resulted in a significant increase in NO: (1.8460.21 mM 1.4860.42 mM, 1.0260.52 mM) (p<0.01, p50.046, p50.26, respectively). CONCLUSIONS: Prolonged, low daytime levels of melatonin increase nitric oxide production from Interferon-gamma stimulated leukocytes and may contribute to seasonal angioedema.
MONDAY
805