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Histamine inhalation challenge in recurrent uvula angioedema
Histamine inhalation challenge in recurrent uvula angioedema To the Editor: Recurrent edema of the uvula is relatively rare and often idiopathic. Possible causes should be excluded, such as allergy, infection, trauma, hereditary angioedema, therapy with angiotensin-converting enzyme inhibitors,1 use of cannabis, 2 and nasal aspiration of parts of the wild cucumber Ecbolium elaterium in some regions of the Mediterranean.3 The diagnosis is obvious when the clinical presentation is of acute upper airway obstruction caused by a large swollen uvula. The case we report here concerns an 18-year-old boy who had chronic progressive uvula edema with recurrent exacerbations, in whom the acute attack could be reproduced by histamine inhalation challenge. The patient was initially seen with recurrent severe attacks of dyspnea that led him frequently to emergency departments (at least 19 times in the past 2 years). The attacks were characterized by a suffocating sensation over the neck, hoarseness, and difficulty in swallowing. On 4 occasions, the patient had undergone fiberoptic rhinolaryngoscopy, which disclosed mild hypertrophy of the nasal turbinates with increased nasal secretions but no laryngeal abnormality. A swollen uvula was reported only twice. When first seen in our clinic, the patient was asymptomatic. Lung function tests were normal, including flow-volume loop, exhaled nitric oxide (10 ppb) and methacholine inhalation challenge (PD20FEV1, 2460 µg). The physical examination was unremarkable, except for the oropharyngeal examination, which disclosed an elongated soft
Letters to the Editor 799
palate and uvula that extended down to the pharynx. The patient denied cigarette smoking, illicit drug abuse, and any other treatment outside attacks. Serum total IgE was 36 IU/mL; serum-specific IgE and prick tests for a wide panel of inhalants and foods were negative. The serum level of complement C4 fraction and C1-esterase inhibitor were in the normal range, and the absolute number of eosinophils in the peripheral blood was 210/µL. The patient referred to episodic postnasal drip, but no radiologic signs of sinusitis were evident at computed tomography scan examination. Histamine inhalation challenge with recording of the flow-volume loop was performed to evaluate the responsiveness of the extrathoracic airway by calculating the decrease of maximum mid-inspiratory flow.4 The test had to be stopped at the third histamine concentration (2 mg/mL) because of severe dyspnea and a marked decrease in both inspiratory and expiratory flows (Fig 1, A). The reaction was associated with a dramatic swelling of the uvula, which recovered within 15 minutes with hypodermic epinephrine spray.5 The patient was given 2 doses of an antihistamine drug (cetirizine, 10 mg), a 2-day tapering course of prednisone, and epinephrine autoinjector (Fastjekt, Merck SpA, Milano, Italy). During the following 2 months, the patient denied further acute attacks of uvula angioedema, but he reported disturbed sleep and daytime somnolence, and his parents said that he had loud snoring. An ambulatory polysomnographic study showed an average of 7 episodes of apnea/hypopnea per hour and snoring that lasted 38% of the total sleeping time. The patient returned to the clinic a few days later in severe respiratory distress, with the sensation of a lump in the back of his throat. He could barely utter some words with a hot-potato voice. His flow-volume loop was similar to that recorded during histamine challenge (Fig 1, B). The throat examination revealed a large swollen uvula that almost completely occluded the pharynx. The reaction recovered within 1 hour after 2 sprays of 0.3 mg hypodermic epinephrine, chlorpheniramine, 4 mg intravenously, and methylprednisolone, 250 mg intravenously. Considering the severity of the dyspneic attacks and the sleep disturbances, the ear, nose, and throat specialist decided to perform uvulopalatoplasty. The histologic examination of the uvula and palate revealed nests of eosinophilic infiltration (Fig 2). One month after surgery, the polysomnographic data were normal (number of apnea and hypopnea episodes per hour = 3, snoring 7% of total sleeping time), and the histamine inhalation challenge was markedly improved, even if a decrease in the maximum mid-inspiratory flow more than 25% of the basal value was still induced by 4.71 mg/mL of histamine (Fig 1, C). When last seen, 8 months after surgery, the patient was asymptomatic. It could not be ascertained what caused the recurrent attacks of uvula angioedema in our patient. The eosinophilic infiltration of the uvula reminds us of other localized eosinophilic infiltrative diseases of the gastrointestinal tract,6 such as eosinophilic esophagitis or gastritis in which the causes are thus far elusive. An inter-
Letters to the editor
J ALLERGY CLIN IMMUNOL VOLUME 112, NUMBER 4
800 Letters to the Editor
J ALLERGY CLIN IMMUNOL OCTOBER 2003
B
A
C
FIG 1. Patterns of the flow-volume loop. A, Before (thin line) and after histamine challenge (thick line). B, During spontaneous uvula angioedema. C, After uvuloplasty, before (thin line) and after histamine challenge (thick line).
Letters to the editor
esting finding in this case is that histamine challenge could reproduce oropharyngeal edema and that this abnormality could be revealed by recording the flow-volume loop. Our observation is very similar to that of Koh and Choi,7 who reported a case of oropharyngeal angioedema induced by inhaled histamine in a patient with asthma who had chronic idiopathic angioedema. Histamine is a potent vasodilator that, in case of enhanced end organ responsiveness, may cause severe angioedema. Histamine challenge with recording of flow-volume loop has been reported to be useful in discriminating those patients with asthma-like symptoms as a result of upper airway diseases.8 Our observation that histamine inhalation challenge may be clinically useful in the evaluation of patients with recurrent oropharyngeal angioedema remains to be investigated.
Supported by the Italian Ministry of University Research (MIUR). Caterina B. Bucca, MDa Luisa Brussino, MDa Andrea Cavalot, MDb Alessandro Cicolin, MDa Giorgio Cortesina, MDb Paolo Baron, MDa Marco Pagano, MDa Giovanni Rolla, MDa aDepartment of Biomedical Sciences and Human Oncology University of Turin Via Genova 3 10126 Torino Italy bDepartment of Clinical Pathophysiology University of Turin
Letters to the Editor 801
FIG 2. A, Histologic picture of the patient’s uvula, showing nests of eosinophils infiltrating the epithelium. B, Histologic picture of the uvula of a subject with sleep apnea but no respiratory symptoms. REFERENCES 1. Kuo DC, Barish RA. Isolated uvular angioedema associated with ACE inhibitor use. J Emerg Med 1995;13:327-30. 2. Boyce SH, Quigley MA. Uvulitis and partial upper airway obstruction following cannabis inhalation. Emerg Med 2002;14:106-8.
3. Satar S, Gokel Y, Toprak N, Sebe A. Life-threatening uvular angioedema caused by Ecbolium elaterium. Eur J Emerg Med 2001;8:337-9. 4. Bucca C, Rolla G, Scappaticci E, Baldi S, Caria E, Oliva A. Histamine hyperresponsiveness of the extrathoracic airway in patients with asthmatic symptoms. Allergy 1991;46:147-53.
Letters to the editor
J ALLERGY CLIN IMMUNOL VOLUME 112, NUMBER 4
802 Letters to the Editor
5. Peltz S, Bateman HE, Reyes R, Oppenheimer J, Bielory L. Hypodermic epinephrine spray and uvular angioedema revisited. J Allergy Clin Immunol 1996;97:717-8. 6. Rothenbert ME, Mishra A, Collins MH, Putnam PE. Pathogenesis and clinical features of eosinophilic esophagitis. J Allergy Clin Immunol 2001;108:891-4. 7. Koh YI, Choi IS. Oropharyngeal angioedema induced by inhaled histamine. J Korean Med Sci 2002;17:830-2. 8. Bucca C, Rolla G, Brussino L, De Rose V, Bugiani M. Are asthma like symptoms due to bronchial or extrathoracic airway dysfunction ? Lancet 1995;346:791-5. doi:10.1067/mai.2003.1702
J ALLERGY CLIN IMMUNOL OCTOBER 2003
Letters to the editor
Letters to the Editor 799
palate and uvula that extended down to the pharynx. The patient denied cigarette smoking, illicit drug abuse, and any other treatment outside attacks. Serum total IgE was 36 IU/mL; serum-specific IgE and prick tests for a wide panel of inhalants and foods were negative. The serum level of complement C4 fraction and C1-esterase inhibitor were in the normal range, and the absolute number of eosinophils in the peripheral blood was 210/µL. The patient referred to episodic postnasal drip, but no radiologic signs of sinusitis were evident at computed tomography scan examination. Histamine inhalation challenge with recording of the flow-volume loop was performed to evaluate the responsiveness of the extrathoracic airway by calculating the decrease of maximum mid-inspiratory flow.4 The test had to be stopped at the third histamine concentration (2 mg/mL) because of severe dyspnea and a marked decrease in both inspiratory and expiratory flows (Fig 1, A). The reaction was associated with a dramatic swelling of the uvula, which recovered within 15 minutes with hypodermic epinephrine spray.5 The patient was given 2 doses of an antihistamine drug (cetirizine, 10 mg), a 2-day tapering course of prednisone, and epinephrine autoinjector (Fastjekt, Merck SpA, Milano, Italy). During the following 2 months, the patient denied further acute attacks of uvula angioedema, but he reported disturbed sleep and daytime somnolence, and his parents said that he had loud snoring. An ambulatory polysomnographic study showed an average of 7 episodes of apnea/hypopnea per hour and snoring that lasted 38% of the total sleeping time. The patient returned to the clinic a few days later in severe respiratory distress, with the sensation of a lump in the back of his throat. He could barely utter some words with a hot-potato voice. His flow-volume loop was similar to that recorded during histamine challenge (Fig 1, B). The throat examination revealed a large swollen uvula that almost completely occluded the pharynx. The reaction recovered within 1 hour after 2 sprays of 0.3 mg hypodermic epinephrine, chlorpheniramine, 4 mg intravenously, and methylprednisolone, 250 mg intravenously. Considering the severity of the dyspneic attacks and the sleep disturbances, the ear, nose, and throat specialist decided to perform uvulopalatoplasty. The histologic examination of the uvula and palate revealed nests of eosinophilic infiltration (Fig 2). One month after surgery, the polysomnographic data were normal (number of apnea and hypopnea episodes per hour = 3, snoring 7% of total sleeping time), and the histamine inhalation challenge was markedly improved, even if a decrease in the maximum mid-inspiratory flow more than 25% of the basal value was still induced by 4.71 mg/mL of histamine (Fig 1, C). When last seen, 8 months after surgery, the patient was asymptomatic. It could not be ascertained what caused the recurrent attacks of uvula angioedema in our patient. The eosinophilic infiltration of the uvula reminds us of other localized eosinophilic infiltrative diseases of the gastrointestinal tract,6 such as eosinophilic esophagitis or gastritis in which the causes are thus far elusive. An inter-
Letters to the editor
J ALLERGY CLIN IMMUNOL VOLUME 112, NUMBER 4
800 Letters to the Editor
J ALLERGY CLIN IMMUNOL OCTOBER 2003
B
A
C
FIG 1. Patterns of the flow-volume loop. A, Before (thin line) and after histamine challenge (thick line). B, During spontaneous uvula angioedema. C, After uvuloplasty, before (thin line) and after histamine challenge (thick line).
Letters to the editor
esting finding in this case is that histamine challenge could reproduce oropharyngeal edema and that this abnormality could be revealed by recording the flow-volume loop. Our observation is very similar to that of Koh and Choi,7 who reported a case of oropharyngeal angioedema induced by inhaled histamine in a patient with asthma who had chronic idiopathic angioedema. Histamine is a potent vasodilator that, in case of enhanced end organ responsiveness, may cause severe angioedema. Histamine challenge with recording of flow-volume loop has been reported to be useful in discriminating those patients with asthma-like symptoms as a result of upper airway diseases.8 Our observation that histamine inhalation challenge may be clinically useful in the evaluation of patients with recurrent oropharyngeal angioedema remains to be investigated.
Supported by the Italian Ministry of University Research (MIUR). Caterina B. Bucca, MDa Luisa Brussino, MDa Andrea Cavalot, MDb Alessandro Cicolin, MDa Giorgio Cortesina, MDb Paolo Baron, MDa Marco Pagano, MDa Giovanni Rolla, MDa aDepartment of Biomedical Sciences and Human Oncology University of Turin Via Genova 3 10126 Torino Italy bDepartment of Clinical Pathophysiology University of Turin
Letters to the Editor 801
FIG 2. A, Histologic picture of the patient’s uvula, showing nests of eosinophils infiltrating the epithelium. B, Histologic picture of the uvula of a subject with sleep apnea but no respiratory symptoms. REFERENCES 1. Kuo DC, Barish RA. Isolated uvular angioedema associated with ACE inhibitor use. J Emerg Med 1995;13:327-30. 2. Boyce SH, Quigley MA. Uvulitis and partial upper airway obstruction following cannabis inhalation. Emerg Med 2002;14:106-8.
3. Satar S, Gokel Y, Toprak N, Sebe A. Life-threatening uvular angioedema caused by Ecbolium elaterium. Eur J Emerg Med 2001;8:337-9. 4. Bucca C, Rolla G, Scappaticci E, Baldi S, Caria E, Oliva A. Histamine hyperresponsiveness of the extrathoracic airway in patients with asthmatic symptoms. Allergy 1991;46:147-53.
Letters to the editor
J ALLERGY CLIN IMMUNOL VOLUME 112, NUMBER 4
802 Letters to the Editor
5. Peltz S, Bateman HE, Reyes R, Oppenheimer J, Bielory L. Hypodermic epinephrine spray and uvular angioedema revisited. J Allergy Clin Immunol 1996;97:717-8. 6. Rothenbert ME, Mishra A, Collins MH, Putnam PE. Pathogenesis and clinical features of eosinophilic esophagitis. J Allergy Clin Immunol 2001;108:891-4. 7. Koh YI, Choi IS. Oropharyngeal angioedema induced by inhaled histamine. J Korean Med Sci 2002;17:830-2. 8. Bucca C, Rolla G, Brussino L, De Rose V, Bugiani M. Are asthma like symptoms due to bronchial or extrathoracic airway dysfunction ? Lancet 1995;346:791-5. doi:10.1067/mai.2003.1702
J ALLERGY CLIN IMMUNOL OCTOBER 2003
Letters to the editor