- Email: [email protected]
Successful treatment of exercise-induced anaphylaxis with omalizumab
S.M. Bray / Ann Allergy Asthma Immunol 109 (2012) 279–285
(reference range, ⬍1,000). Intravenous methylprednisolone 4 mg/ kg/day was started on day 17 of hospitalization and gradually weaned to 2 mg/kg/day over 2 weeks until discharge home in good condition. Echocardiogram obtained before discharge was unremarkable. She did not return for scheduled follow-up care, and 18 days after discharge developed respiratory and cardiac arrest at home and died. She was reported to have been ill for 1 week prior with rash and fever. Review of the bone marrow biopsy obtained during her illness showed myeloid predominance of eosinophilic lineage similar to a previous report of DRESS2 but also showed nonnecrotizing loose granulomas and numerous reactive lymphocytes (Fig 1). Because of the unclear cause of her death, an autopsy was performed. Her heart was enlarged, and granulomatous necrotizing inflammation with eosinophils characteristic of necrotizing eosinophilic myocarditis was identified (Fig 1). Pulmonary edema consistent with acute congestive heart failure without bronchopneumonia also was found. Based on her prior clinical and laboratory evidences of DRESS and the cardiac pathologic condition, her cause of death likely was DRESS-associated myocarditis and cardiac failure. In this case, the latency between drug exposure and onset of symptom, elevated sCD25, predominance of peripheral T cells, and activated tissue lymphocytes all support the role for a T-cell–mediated inflammatory process in DRESS. Indeed, a study by Picard et al3 demonstrated elevated numbers of activated CD8⫹ T cells and increased production of cytokines from the CD8⫹ T cells in DRESS patients. A case report of sulfasalazine-induced DRESS and fulminant liver failure after additional vancomycin treatment also demonstrated postmortem that the liver was infiltrated with activated CD8⫹CD3⫹ T lymphocytes, again suggesting a strong role for activated T cells in disease pathogenesis.4 Although whether the T cells in our patient were CD8⫹ is not known, strong evidence of T cell activation was seen based on histology and elevated sCD25, consistent with these prior reports.3,4 Serum sCD25 is a marker of peripheral blood T cell activation and is increased in certain hematologic malignancies and several autoimmune diseases.5 sCD25 is 1 of the laboratory criteria used to diagnose hemophagocytic lymphocytic histiocytosis (HLH).6 Although this patient did meet criteria for HLH with fever, splenomegaly, thrombocytopenia, ferritin greater than 500 g/L, and elevated sCD25, no morphologic evidence of hemophagocytosis was present, and the ferritin was not as elevated as typically seen in this syndrome. However, DRESS and drug-induced HLH both appear to be caused by uncontrolled T-cell activation and are treated similarly, with immune suppression and removal of the offending agent. Thus, DRESS and drug-induced HLH may represent a spectrum of the same disorder. Studying the cytotoxic function of
281
lymphocytes from patients with DRESS will be interesting, because this is known to be abnormal in patients with HLH.7 Only 13 case reports of vancomycin-induced DRESS have been reported to date and only 1 prior report in pediatrics.8 This case exemplifies that DRESS is a rare but life-threatening condition. The predominance of peripheral T-cells with marked elevation of sCD25 in this patient supports the role of T cell activation in the pathogenesis of this syndrome. Maleewan Kitcharoensakkul, MD* Nicholas Ree, DO† Gordon R. Bloomberg, MD* Louis P. Dehner, MD† John A. Heidingsfelder, MD‡ Andrew J. White, MSc, MD* Megan A. Cooper, MD, PhD* *Department of Pediatrics St. Louis Children’s Hospital Washington University School of Medicine St. Louis, Missouri † Department of Pathology and Immunology Barnes-Jewish and St. Louis Children’s Hospitals Washington University School of Medicine St. Louis, Missouri ‡ Forensic Pathology Service Utica, Kentucky [email protected]
References [1] Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol. 2007;156:609 – 611. [2] Lee JH, Park HK, Heo J, et al. Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome induced by celecoxib and anti-tuberculosis drugs. J Korean Med Sci. 2008;23:521–525. [3] Picard D, Janela B, Descamps V, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response. Sci Transl Med. 2010;2:46 – 62. [4] Mennicke M, Zawodniak A, Keller M, et al. Fulminant liver failure after vancomycin in a sulfasalazine-induced DRESS syndrome: fatal recurrence after liver transplantation. Am J Transplant. 2009;9:2197–2202. [5] Rubin LA, Nelson DL. The soluble interleukin-2 receptor: biology, function, and clinical application. Ann Intern Med. 1990;113:619 – 627. [6] Gupta S, Weitzman S. Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy. Expert Rev Clin Immunol. 2010;6:137–154. [7] Perez N, Virelizier JL, Arenzana-Seisdedos F, Fischer A, Griscelli C. Impaired natural killer activity in lymphohistiocytosis syndrome. J Pediatr. 1984;104: 569 –573. [8] Vinson AE, Dufort EM, Willis MD, Eberson CP, Harwell JI. Drug rash, eosinophilia, and systemic symptoms syndrome: Two pediatric cases demonstrating the range of severity in presentation—a case of vancomycin-induced drug hypersensitivity mimicking toxic shock syndrome and a milder case induced by minocycline. Pediatr Crit Care Med. 2010;11:e38⫺43.
Successful treatment of exercise-induced anaphylaxis with omalizumab Omalizumab, a monoclonal antibody against immunoglobulin E (IgE), is approved for the treatment of moderate to severe allergic asthma. Furthermore, case reports have documented its successful use in the treatment of anaphylaxis of various causes: idiopathic,1,2 systemic mastocytosis,3 and venom induced.4,5 To date, omalizumab has not been reported in the treatment of exercise-induced anaphylaxis (EIA). Exercise-induced anaphylaxis is a potentially life-threatening clinical syndrome, manifesting with a variety of symptoms occurring during or Disclosures: Dr. Petrov received research support from Genentech from 2004 – 2012. The remaining authors have nothing to disclose.
shortly after exercise. EIA can occur independently or in association with specific food ingestion, known as food-dependent exercise-induced anaphylaxis (FDEIA). The pathophysiology of both EIA and FDEIA is not fully understood, but it is likely mediated by mast cell degranulation with histamine release.6 Current preventative treatments include exercise avoidance, food avoidance in FDEIA, and pretreatment with medications such as antihistamines, cromolyn, or montelukast before exercise.7 At the time of this manuscript’s writing, this is the first successful off-label use of omalizumab in the prevention of EIA. A 14-year-old male competitive athlete, with a history of EIA and allergic rhinitis, presented to the University Allergy Clinic after 2 episodes
282
Letters / Ann Allergy Asthma Immunol 109 (2012) 279–285
of anaphylaxis after running. Two hours before the initial episode, he had eaten a full meal, which consisted of milk, hamburger, celery with peanut butter, orange, and banana. His symptoms included diffuse redness with itching, facial angioedema, lightheadedness, and hypotension (blood pressure ⫽ 70/50 mmHg), which began 5 minutes after completing a 1-hour run. In the emergency room, he received intramuscular epinephrine, intravenous methylprednisolone, diphenhydramine, and famotidine. On discharge, he was started on daily cetirizine and given an injectable epinephrine kit. He has never had a history of food-allergy. Nevertheless, he underwent evaluation for a food-induced trigger. The skin testing was positive to celery and peanut. Serologic testing was significant for elevated specific IgE to peanut, apple, barley, oat, rice, soy, wheat, orange, banana, beef, and celery (all values were class I or class II positive). Total IgE level was 235 IU/mL. He was instructed not to eat these foods before running. He continued to exercise without difficulty, until 5 weeks later, when he had a second episode of anaphylaxis 5 minutes after completing a 3-mile race. Thirty minutes before exercise, he had eaten a chocolate-flavored nutritional bar. He received 2 epinephrine doses in the field and was taken to the emergency room, where he received additional treatment with intravenous steroids and antihistamines. He was subsequently referred to our center, where he was started on montelukast 10 mg, fexofenadine 180 mg, cromolyn 200 mg, and ranitidine 150 mg 2 hours before exercise. Additionally, he was instructed to avoid all foods 6 hours before exercise. Baseline tryptase was normal (4 ng/mL). Despite these measures, he continued to have breakthrough anaphylactic reactions with even minimal exercise (playing frisbee) and once, after ingestion of 200 mg ibuprofen. The patient was subsequently instructed to avoid all nonsteroidal anti-inflammatory medications and to stop exercise completely. Dietary and activity restriction were very difficult for this young high school athlete. He opted to participate in weight lifting over the next 2 months, which caused recurrent facial swelling. Given his refractory symptoms, a decision was made to add omalizumab therapy (300 mg monthly) to his maintenance therapies. Four months after the onset of treatment, the patient resumed exercise activity. He did not change his premedication regimen, but he resumed eating before exercise without any restrictions. His daily exercise consisted of 2 hours of combined anaerobic and aerobic activity in the gym: warm-up sessions, weight lifting, and intermittent cardio-exercises; however, he has
not resumed competitive running. He was able to tolerate all these activities without difficulty with no epinephrine use or emergency room visits. He continues to receive monthly treatments. This is the first case report of the successful use of omalizumab in the treatment of EIA. The pathophysiology of EIA remains unknown. In addition to IgE-mediated mast cell degranulation, other proposed mechanisms include exercise-induced changes in plasma osmolality, alterations in blood pH, alteration in tissue transglutaminase, redistribution of blood flow and antigen presentation, and changes in gut permeability.6,7 Omalizumab has been previously shown to treat anaphylaxis in case reports.1⫺3 In these cases, the proposed mechanism of omalizumab action was to decrease serum concentration of IgE as well as stabilize mast cells by downregulating the expression of the high-affinity IgE receptor. Although omalizumab does not target all proposed pathways in EIA, its mast cell stabilizing effect likely contributed to the clinical response in this patient. Sarah M. Bray, MD* Merritt L. Fajt, MD† Andrej A. Petrov, MD† *Department of Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania † Division of Pulmonary, Allergy, and Critical Care Medicine Department of Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected] References [1] Jones JD, Marney SR Jr, Fahrenholz JM. Idiopathic anaphylaxis successfully treated with omalizumab. Ann Allergy Asthma Immunol. 2008;101:550 –551. [2] Warrier P, Casale TB. Omalizumab in idiopathic anaphylaxis. Ann Allergy Asthma Immunol. 2009;102:257–258. [3] Carter MC, Robyn JA, Bressler PB, Walker JC, Shapiro GG, Metcalfe DD. Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis. J Allergy Immunol. 2007;119:1550 –1551. [4] Tartibi HM, Majmundar AR, Khan DA. Successful use of omalizumab for prevention of fire ant anaphylaxis. J Allergy Clin Immunology. 2010;126:664 – 665. [5] Schulze J, Rose M, Zielen S. Beekeepers anaphylaxis: successful immunotherapy covered by omalizumab. Allergy. 2007;62:963–964. [6] Wojciech B, Wojciech M, Wolanczyk-Medrala A. Exercise-induced anaphylaxis: an update on diagnosis and treatment. Curr Allergy Asthma Rep. 2011;11:45–51. [7] Robson-Ansley P, Toit GD. Pathophysiology, diagnosis, and management of exerciseinduced anaphylaxis. Curr Opin Allergy Clin Immunol. 2010;10:312–317.
Exercise-induced hyperventilation: more common than appreciated Exercise-induced respiratory symptoms, especially in adolescents, are common and are often not caused by asthma.1 Hyperventilation during exercise, breathing in excess of exercise metabolic requirements, is a cause of pseudoasthma,2 usually erroneously attributed to exercise-induced bronchoconstriction (EIB). We recently treated an adolescent with exercise-induced hyperventilation and identified 11 more individuals in 18 months with similar clinical features. A 15-year-old nonsmoking female student (Table 1, #1) had left home to attend ballet school 6 months before presenting to us. She developed breathlessness with strenuous exertion, difficulty getting air in, chest tightness, and associated lightheadedness, headaches, and weakness. Symptoms were nonresponsive to bronchodilators and inhaled corticosteroids. Voluntary hyperventilation while at school reproduced all her symptoms. Despite this, on return to Saskatoon, she was referred for management of refractory asthma. She had no rhinitis or other health problems, was using no
Disclosures: Authors have nothing to disclose.
medications, and had normal results of physical examination (oxygen saturation, 100%). Chest radiograph, pulmonary function including maximal inspiratory flows, and methacholine challenge3 (provocation concentration causing a 20% fall in FEV1 [PC20] ⬎ 16 mg/mL) were normal; she was non-atopic. Exercise testing failed to produce symptoms, bronchospasm or hyperventilation. A diagnosis of exercise-induced hyperventilation was made based on the history, the exclusion of asthma, and the hyperventilation response. We subsequently over 18 months identified 11 young athletic individuals (10 female) with similar symptoms (Table 1, #2–12). All had breathlessness on strenuous exertion with a sensation of difficulty on inspiration and either syncope (n ⫽ 4) or presyncope (n ⫽ 8). None of the patients described stridor, none had gastroesophageal reflux disease symptoms, and none had any respiratory symptoms at any other times. Paresthesia accompanied the respiratory symptoms in 4. Three reported symptoms occurring only during competition and not during practice involving equivalent exercise. When the suspected diagnosis was
(reference range, ⬍1,000). Intravenous methylprednisolone 4 mg/ kg/day was started on day 17 of hospitalization and gradually weaned to 2 mg/kg/day over 2 weeks until discharge home in good condition. Echocardiogram obtained before discharge was unremarkable. She did not return for scheduled follow-up care, and 18 days after discharge developed respiratory and cardiac arrest at home and died. She was reported to have been ill for 1 week prior with rash and fever. Review of the bone marrow biopsy obtained during her illness showed myeloid predominance of eosinophilic lineage similar to a previous report of DRESS2 but also showed nonnecrotizing loose granulomas and numerous reactive lymphocytes (Fig 1). Because of the unclear cause of her death, an autopsy was performed. Her heart was enlarged, and granulomatous necrotizing inflammation with eosinophils characteristic of necrotizing eosinophilic myocarditis was identified (Fig 1). Pulmonary edema consistent with acute congestive heart failure without bronchopneumonia also was found. Based on her prior clinical and laboratory evidences of DRESS and the cardiac pathologic condition, her cause of death likely was DRESS-associated myocarditis and cardiac failure. In this case, the latency between drug exposure and onset of symptom, elevated sCD25, predominance of peripheral T cells, and activated tissue lymphocytes all support the role for a T-cell–mediated inflammatory process in DRESS. Indeed, a study by Picard et al3 demonstrated elevated numbers of activated CD8⫹ T cells and increased production of cytokines from the CD8⫹ T cells in DRESS patients. A case report of sulfasalazine-induced DRESS and fulminant liver failure after additional vancomycin treatment also demonstrated postmortem that the liver was infiltrated with activated CD8⫹CD3⫹ T lymphocytes, again suggesting a strong role for activated T cells in disease pathogenesis.4 Although whether the T cells in our patient were CD8⫹ is not known, strong evidence of T cell activation was seen based on histology and elevated sCD25, consistent with these prior reports.3,4 Serum sCD25 is a marker of peripheral blood T cell activation and is increased in certain hematologic malignancies and several autoimmune diseases.5 sCD25 is 1 of the laboratory criteria used to diagnose hemophagocytic lymphocytic histiocytosis (HLH).6 Although this patient did meet criteria for HLH with fever, splenomegaly, thrombocytopenia, ferritin greater than 500 g/L, and elevated sCD25, no morphologic evidence of hemophagocytosis was present, and the ferritin was not as elevated as typically seen in this syndrome. However, DRESS and drug-induced HLH both appear to be caused by uncontrolled T-cell activation and are treated similarly, with immune suppression and removal of the offending agent. Thus, DRESS and drug-induced HLH may represent a spectrum of the same disorder. Studying the cytotoxic function of
281
lymphocytes from patients with DRESS will be interesting, because this is known to be abnormal in patients with HLH.7 Only 13 case reports of vancomycin-induced DRESS have been reported to date and only 1 prior report in pediatrics.8 This case exemplifies that DRESS is a rare but life-threatening condition. The predominance of peripheral T-cells with marked elevation of sCD25 in this patient supports the role of T cell activation in the pathogenesis of this syndrome. Maleewan Kitcharoensakkul, MD* Nicholas Ree, DO† Gordon R. Bloomberg, MD* Louis P. Dehner, MD† John A. Heidingsfelder, MD‡ Andrew J. White, MSc, MD* Megan A. Cooper, MD, PhD* *Department of Pediatrics St. Louis Children’s Hospital Washington University School of Medicine St. Louis, Missouri † Department of Pathology and Immunology Barnes-Jewish and St. Louis Children’s Hospitals Washington University School of Medicine St. Louis, Missouri ‡ Forensic Pathology Service Utica, Kentucky [email protected]
References [1] Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol. 2007;156:609 – 611. [2] Lee JH, Park HK, Heo J, et al. Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome induced by celecoxib and anti-tuberculosis drugs. J Korean Med Sci. 2008;23:521–525. [3] Picard D, Janela B, Descamps V, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response. Sci Transl Med. 2010;2:46 – 62. [4] Mennicke M, Zawodniak A, Keller M, et al. Fulminant liver failure after vancomycin in a sulfasalazine-induced DRESS syndrome: fatal recurrence after liver transplantation. Am J Transplant. 2009;9:2197–2202. [5] Rubin LA, Nelson DL. The soluble interleukin-2 receptor: biology, function, and clinical application. Ann Intern Med. 1990;113:619 – 627. [6] Gupta S, Weitzman S. Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy. Expert Rev Clin Immunol. 2010;6:137–154. [7] Perez N, Virelizier JL, Arenzana-Seisdedos F, Fischer A, Griscelli C. Impaired natural killer activity in lymphohistiocytosis syndrome. J Pediatr. 1984;104: 569 –573. [8] Vinson AE, Dufort EM, Willis MD, Eberson CP, Harwell JI. Drug rash, eosinophilia, and systemic symptoms syndrome: Two pediatric cases demonstrating the range of severity in presentation—a case of vancomycin-induced drug hypersensitivity mimicking toxic shock syndrome and a milder case induced by minocycline. Pediatr Crit Care Med. 2010;11:e38⫺43.
Successful treatment of exercise-induced anaphylaxis with omalizumab Omalizumab, a monoclonal antibody against immunoglobulin E (IgE), is approved for the treatment of moderate to severe allergic asthma. Furthermore, case reports have documented its successful use in the treatment of anaphylaxis of various causes: idiopathic,1,2 systemic mastocytosis,3 and venom induced.4,5 To date, omalizumab has not been reported in the treatment of exercise-induced anaphylaxis (EIA). Exercise-induced anaphylaxis is a potentially life-threatening clinical syndrome, manifesting with a variety of symptoms occurring during or Disclosures: Dr. Petrov received research support from Genentech from 2004 – 2012. The remaining authors have nothing to disclose.
shortly after exercise. EIA can occur independently or in association with specific food ingestion, known as food-dependent exercise-induced anaphylaxis (FDEIA). The pathophysiology of both EIA and FDEIA is not fully understood, but it is likely mediated by mast cell degranulation with histamine release.6 Current preventative treatments include exercise avoidance, food avoidance in FDEIA, and pretreatment with medications such as antihistamines, cromolyn, or montelukast before exercise.7 At the time of this manuscript’s writing, this is the first successful off-label use of omalizumab in the prevention of EIA. A 14-year-old male competitive athlete, with a history of EIA and allergic rhinitis, presented to the University Allergy Clinic after 2 episodes
282
Letters / Ann Allergy Asthma Immunol 109 (2012) 279–285
of anaphylaxis after running. Two hours before the initial episode, he had eaten a full meal, which consisted of milk, hamburger, celery with peanut butter, orange, and banana. His symptoms included diffuse redness with itching, facial angioedema, lightheadedness, and hypotension (blood pressure ⫽ 70/50 mmHg), which began 5 minutes after completing a 1-hour run. In the emergency room, he received intramuscular epinephrine, intravenous methylprednisolone, diphenhydramine, and famotidine. On discharge, he was started on daily cetirizine and given an injectable epinephrine kit. He has never had a history of food-allergy. Nevertheless, he underwent evaluation for a food-induced trigger. The skin testing was positive to celery and peanut. Serologic testing was significant for elevated specific IgE to peanut, apple, barley, oat, rice, soy, wheat, orange, banana, beef, and celery (all values were class I or class II positive). Total IgE level was 235 IU/mL. He was instructed not to eat these foods before running. He continued to exercise without difficulty, until 5 weeks later, when he had a second episode of anaphylaxis 5 minutes after completing a 3-mile race. Thirty minutes before exercise, he had eaten a chocolate-flavored nutritional bar. He received 2 epinephrine doses in the field and was taken to the emergency room, where he received additional treatment with intravenous steroids and antihistamines. He was subsequently referred to our center, where he was started on montelukast 10 mg, fexofenadine 180 mg, cromolyn 200 mg, and ranitidine 150 mg 2 hours before exercise. Additionally, he was instructed to avoid all foods 6 hours before exercise. Baseline tryptase was normal (4 ng/mL). Despite these measures, he continued to have breakthrough anaphylactic reactions with even minimal exercise (playing frisbee) and once, after ingestion of 200 mg ibuprofen. The patient was subsequently instructed to avoid all nonsteroidal anti-inflammatory medications and to stop exercise completely. Dietary and activity restriction were very difficult for this young high school athlete. He opted to participate in weight lifting over the next 2 months, which caused recurrent facial swelling. Given his refractory symptoms, a decision was made to add omalizumab therapy (300 mg monthly) to his maintenance therapies. Four months after the onset of treatment, the patient resumed exercise activity. He did not change his premedication regimen, but he resumed eating before exercise without any restrictions. His daily exercise consisted of 2 hours of combined anaerobic and aerobic activity in the gym: warm-up sessions, weight lifting, and intermittent cardio-exercises; however, he has
not resumed competitive running. He was able to tolerate all these activities without difficulty with no epinephrine use or emergency room visits. He continues to receive monthly treatments. This is the first case report of the successful use of omalizumab in the treatment of EIA. The pathophysiology of EIA remains unknown. In addition to IgE-mediated mast cell degranulation, other proposed mechanisms include exercise-induced changes in plasma osmolality, alterations in blood pH, alteration in tissue transglutaminase, redistribution of blood flow and antigen presentation, and changes in gut permeability.6,7 Omalizumab has been previously shown to treat anaphylaxis in case reports.1⫺3 In these cases, the proposed mechanism of omalizumab action was to decrease serum concentration of IgE as well as stabilize mast cells by downregulating the expression of the high-affinity IgE receptor. Although omalizumab does not target all proposed pathways in EIA, its mast cell stabilizing effect likely contributed to the clinical response in this patient. Sarah M. Bray, MD* Merritt L. Fajt, MD† Andrej A. Petrov, MD† *Department of Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania † Division of Pulmonary, Allergy, and Critical Care Medicine Department of Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania [email protected] References [1] Jones JD, Marney SR Jr, Fahrenholz JM. Idiopathic anaphylaxis successfully treated with omalizumab. Ann Allergy Asthma Immunol. 2008;101:550 –551. [2] Warrier P, Casale TB. Omalizumab in idiopathic anaphylaxis. Ann Allergy Asthma Immunol. 2009;102:257–258. [3] Carter MC, Robyn JA, Bressler PB, Walker JC, Shapiro GG, Metcalfe DD. Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis. J Allergy Immunol. 2007;119:1550 –1551. [4] Tartibi HM, Majmundar AR, Khan DA. Successful use of omalizumab for prevention of fire ant anaphylaxis. J Allergy Clin Immunology. 2010;126:664 – 665. [5] Schulze J, Rose M, Zielen S. Beekeepers anaphylaxis: successful immunotherapy covered by omalizumab. Allergy. 2007;62:963–964. [6] Wojciech B, Wojciech M, Wolanczyk-Medrala A. Exercise-induced anaphylaxis: an update on diagnosis and treatment. Curr Allergy Asthma Rep. 2011;11:45–51. [7] Robson-Ansley P, Toit GD. Pathophysiology, diagnosis, and management of exerciseinduced anaphylaxis. Curr Opin Allergy Clin Immunol. 2010;10:312–317.
Exercise-induced hyperventilation: more common than appreciated Exercise-induced respiratory symptoms, especially in adolescents, are common and are often not caused by asthma.1 Hyperventilation during exercise, breathing in excess of exercise metabolic requirements, is a cause of pseudoasthma,2 usually erroneously attributed to exercise-induced bronchoconstriction (EIB). We recently treated an adolescent with exercise-induced hyperventilation and identified 11 more individuals in 18 months with similar clinical features. A 15-year-old nonsmoking female student (Table 1, #1) had left home to attend ballet school 6 months before presenting to us. She developed breathlessness with strenuous exertion, difficulty getting air in, chest tightness, and associated lightheadedness, headaches, and weakness. Symptoms were nonresponsive to bronchodilators and inhaled corticosteroids. Voluntary hyperventilation while at school reproduced all her symptoms. Despite this, on return to Saskatoon, she was referred for management of refractory asthma. She had no rhinitis or other health problems, was using no
Disclosures: Authors have nothing to disclose.
medications, and had normal results of physical examination (oxygen saturation, 100%). Chest radiograph, pulmonary function including maximal inspiratory flows, and methacholine challenge3 (provocation concentration causing a 20% fall in FEV1 [PC20] ⬎ 16 mg/mL) were normal; she was non-atopic. Exercise testing failed to produce symptoms, bronchospasm or hyperventilation. A diagnosis of exercise-induced hyperventilation was made based on the history, the exclusion of asthma, and the hyperventilation response. We subsequently over 18 months identified 11 young athletic individuals (10 female) with similar symptoms (Table 1, #2–12). All had breathlessness on strenuous exertion with a sensation of difficulty on inspiration and either syncope (n ⫽ 4) or presyncope (n ⫽ 8). None of the patients described stridor, none had gastroesophageal reflux disease symptoms, and none had any respiratory symptoms at any other times. Paresthesia accompanied the respiratory symptoms in 4. Three reported symptoms occurring only during competition and not during practice involving equivalent exercise. When the suspected diagnosis was