- Email: [email protected]
Exercise-induced hyperventilation: more common than appreciated
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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
⫹⫹ ⫹ ⫹⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ 14 18F 37F 26F 15F 23F 16F 14F 16M 4 5 6 7 8 9 10 11 12
Abbreviations: FEV1, forced expired volume in 1 second (% predicted); PC20, provocation concentration causing a 20% FEV1 fall; PetCO2, end-tidal partial pressure of CO2 (mmHg); ND, not done; NT, not tried; PIF, peak inspiratory flow. a Symptoms induced by methacholine did NOT mimic those induced by exercise.
34 35
38
ND 30 ND ND ND ND ND 32 38 ND Normal ND ND ND ND ND Normal Normal 1.3 14 ⬎16 ⬎16 8 ⬎16 4a 5a ⬎16 3.7 6.0 3.0 5.4 5.9 5.8 5.2 4.2 6.9 98 112 121 115 115 84 104 82 100 100 99 98 99 100 99 99 99 98 No No No No No No mild Cat exposure No ⫺ NT NT NT ⫺ NT NT ⫺ ⫾ ⫺ ⫺ ⫾ ⫺ ⫺ ⫺ ⫺ ⫺ ⫾
3.9 4.2 5.3 91 94 116 100 98 99 No No No ⫺ NT ⫺ ⫺ ⫾ ⫺ 15F 16F 15F 1 2 3
Ballet Track Taekwondo basketball Soccer Exercise 10 K run Exercise Swimming Exercise Track Soccer basketball Kayak
⫹ ⫹⫹ ⫹⫹
⫺ ⫺ ⫹
ICS BD
⫹ ⫹ ⫹
⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺ ⫹
36 35 37 Normal Normal Normal ⬎16 6a 12
Meth PC20 (mg/mL) PIF (L/s) FEV1 (%) Resting oxygen saturation Rhinitis Response to asthma therapy Paresthesia Presyncope (⫹) or syncope (⫹⫹) Difficulty inspiring Activity Age sex #
Table 1 Clinical characteristics and laboratory data
34 34 36
Rest
Exercise test
PetCO2
Exercise
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283
discussed with these patients, none admitted to pre-exercise hyperventilation, a technique believed by some to preload oxygen stores to help improve performance. Asthma was suspected in all; response to bronchodilators (n ⫽ 12) or inhaled corticosteroids (n ⫽ 6, Table 1) was absent (n ⫽ 9) or equivocal (n ⫽ 3). Rhinitis was absent except for 1 with mild perennial rhinitis and 1 with rhinitis on cat exposure. Resting oxygen saturations were uniformly high (98 –100%). Three of these patients had elevated room air oxygen saturations (98 –99%) in emergency rooms during attacks. Inspiratory and expiratory flows were normal (Table 1), and methacholine PC20 was normal (⬎8 mg/mL) in 8, and mildly (n ⫽ 1) to borderline (n ⫽ 3) reduced in 4. In 3 subjects with borderline airway hyper-responsiveness, the methacholine-induced symptoms did not mimic those that occurred with exertion. Exercise testing was done in 6; none developed EIB or hyperventilation, and symptoms were not reproduced. End-tidal partial pressure of carbon dioxide was low normal (30 –35 mmHg) and did not fall after exercise. None of the additional 11 patients was challenged with voluntary hyperventilation. We present 12 patients with non-asthmatic exercise-induced dyspnea. We suspected exercise hyperventilation but were unable to objectively confirm this in 11 of 12. The clinical clues suggesting hyperventilation include difficulty with inspiration, high resting oxygen saturation, absence of rhinitis or nocturnal symptoms, and poor response to bronchodilators. Paresthesia (n ⫽ 4) and syncope (n ⫽ 4)/presyncope (n ⫽ 8) are particularly suggestive of hyperventilation with acute respiratory alkalosis. Asthma was excluded by a normal methacholine test in most subjects, and in those who did respond to methacholine (mild or borderline) the methacholineinduced symptoms did not mimic the exercise symptoms. Possibly in this latter subset, minor bronchoconstriction might have contributed to the hyperventilation. Symptoms4,5 may be more accurate than the hyperventilation test6 in identifying hyperventilation. The gold standard for identifying exercise-induced hyperventilation would be an exercise test positive for hyperventilation with low end-tidal CO2.2 However, exercise under supervision may not reproduce symptoms or cause hyperventilation2; we suspect this may be similar to the failure to reproduce the symptom complex during practice compared with competition. Intermittent laryngeal dysfunction during exercise could produce somewhat similar symptoms,1,7 particularly difficulty with inspiration. This could not be entirely excluded in our patients. None had stridor, inspiratory flows were normal, and none developed typical attacks, stridor, or decrease in inspiratory flows during methacholine (n ⫽ 12) or exercise (n ⫽ 6) testing. However, laryngeal dysfunction can be intermittent, and normal inspiratory flow when asymptomatic does not exclude this possibility; the major diagnostic tool, fiberoptic laryngoscopy during exercise, is not routinely available. Because our subjects did not develop symptoms or inspiratory flow limitation during exercise, laryngoscopy is unlikely to have been abnormal. None of the other differential diagnoses as outlined in the EIB practice parameter7 seems plausible in these individuals. Treatment strategies include education regarding the mechanism of symptom generation secondary to hypocapnea and respiratory alkalosis and reassurance that there is no underlying organic cause of their symptoms. Breathing retraining has been suggested as a treatment for hyperventilation.8 This was attempted in 1 patient (#2) with limited success. Pharmacotherapy has limited value. In summary, we were able to identify 12 individuals suspected of exercise-induced hyperventilation. This condition, and other nonasthmatic causes of exercise limitation (eg, laryngeal dysfunction), may be more common than is generally appreciated. We recommend that clinicians dealing with asthma or exercise keep
284
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this possibility in mind when dealing with exercise-induced breathlessness. Mohammed AlShati, MD, FRCP(C) Donald W. Cockcroft, MD, FRCP(C) Mark E. Fenton, MD, FRCP(C) Division of Respirology Critical Care and Sleep Medicine University of Saskatchewan Saskatoon, Saskatchewan, Canada [email protected] References [1] Tilles SW. Exercise-induced respiratory symptoms: an epidemic among adolescents. Ann Allergy Asthma Immunol. 2010;104:361–367.
[2] Hammo AH, Weinberger MM. Exercise-induced hyperventilation: a psuedoasthma syndrome. Ann Allergy Asthma Immunol. 1999;82:574 –578. [3] Cockcroft DW, Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy. 1977;7:235– 243. [4] Van Dixhoorn J, Duivenvoorden HJ. Efficacy of Nijmegen questionnaire in recognition of the hyperventilation syndrome. J Psychosom Res. 1985;29:199 –206. [5] Grossman P, De Swart JCG. Diagnosis of hyperventilation syndrome on the basis of reported complaints. J Psychosom Res. 1984;28:97–104. [6] Hornsveld HK, Garssen B. Double-blind placebo-controlled study of the hyperventilation provocation test and the validity of the hyperventilation syndrome. Lancet. 1996;348:145–148. [7] Weiler JM, Anderson SA, Bonini S, et al. Pathogenesis, prevalence, diagnosis and management of exercise-induced bronchoconstriction: a practice parameter. Ann Allergy Asthma Immunol. 2010;105:S1–S47. [8] Han JN, Stegen K, De Valck C, Clement J, Van de Woestijne KP. Influence of breathing therapy on complaints, anxiety and breathing pattern in patients with hyperventilation syndrome and anxiety disorders. J Psychosom Res. 1996;41:481– 493.
Successful sirolimus graded dose challenge in an erythromycin-allergic patient Most macrolides are broad-spectrum antibiotics commonly used for the treatment of upper respiratory tract infections. Tacrolimus, sirolimus, everolimus, and temsirolimus are among the newest macrolides used for the prevention and treatment of acute rejection after solid organ transplantation and graft versus host disease after hematopoietic stem cell transplantation. Allergic reactions to macrolide antibiotics include urticaria, angioedema, anaphylaxis, Stevens-Johnson syndrome, and toxic epidermal necrolysis and are uncommon (0.4 – 3%).1 Hypersensitivity reactions to immunosuppressive macrolides are also rare, with only a few cases of sirolimus- and everolimus-associated angioedema reported.2,3 Poor understanding exists between the cross-reactivity among macrolides, especially among newer immunosuppressants; at least 1 hypersensitivity reaction has been described with use of tacrolimus in a clarithromycin-allergic patient.4 Herein, we describe a patient with erythromycin allergy who underwent successful graded dose challenge to sirolimus. A 37-year-old woman with a history of relapsed and refractory human T-lymphotropic virus-1–associated adult T cell lymphoma was admitted to the hospital for reduced-intensity human leukocyte antigen–matched sibling peripheral blood stem cell transplantation. Treatment on study protocol, NCT00074490, included a conditioning regimen of fludarabine and cyclophosphamide. Graft-versus-host disease prophylaxis consisted of sirolimus and cyclosporine, both initiated 4 days before transplantation. The patient’s medical history was significant for macrolide allergy. Two years prior, she recalled developing diffuse pruritus with the first 2 doses of a twice-daily erythromycin course prescribed for lymphadenitis; the pruritus was treated symptomatically with loratadine. One hour after the third dose, she again developed diffuse pruritus but also had urticaria, shortness of breath, and throat swelling. These symptoms resolved with administration of diphenhydramine and prednisone. Because of these symptoms, antibiotics were discontinued. Before this reaction, she had tolerated treatment with azithromycin. Nonirritating doses of erythromycin were used for evaluation 2 years after the initial reaction.5 Erythromycin was prepared using the intravenous solution. Results of skin prick test and intradermal test to erythromycin (0.05 mg/mL) were negative. Saline control was negative, and histamine (6 mg/mL) was positive, with 10-mm wheal and 40-mm flare.
Disclosures: Authors have nothing to disclose. Funding Sources: This work was supported by the Division of Intramural Research, National Institute of Allergic and Infectious Diseases and the National Cancer Institute, National Institutes of Health.
Table 1 Sirolimus oral graded dose challenge protocol Dose number
Concentration
Dose (mg)
1 2 3
1:100 1:10 1:1
0.16 1.5 14
Sirolimus oral solution 1 mg/mL was used for doses 1 and 2. Seven 2-mg oral tablets were administered simultaneously for dose 3.
Erythromycin skin testing is not validated, and a negative result does not rule out the presence of drug-specific immunoglobulin E antibodies. This patient’s reaction was consistent with a hypersensitivity reaction and therefore concerning. Because the study protocol on which she was enrolled was specifically investigating the biological and clinical effects of sirolimus, the drug could not be easily substituted. Because the cross-reactivity among macrolides is largely unknown, a graded-dose challenge was performed (Table 1). After providing informed consent, the patient orally received 1/100th of the target sirolimus loading dose (16 mg). Individual doses were administered at 30-minute intervals across 1.5 hours. No adverse reaction developed, and the patient was able to receive a total cumulative 16-mg dose of sirolimus. She began routine administration of sirolimus at the protocol-determined maintenance dose of 8 mg daily (goal level 20–30 ng/mL). She tolerated treatment without any adverse effects. Immediate reactions to macrolides are rarely reported, with diagnosis primarily relying on clinical history alone. Unfortunately, results of macrolide skin and in vitro testing often yield negative results. As shown by Seitz et al,6 only 1 patient of 125 with suspected hypersensitivity to a macrolide based on history alone tested positive to allergological testing.6 Clinical cross-reactivity among macrolides is largely unknown, with few published cases (reviewed in Seitz et al6). A large lactone ring with varying numbers of atoms is the main structural component of macrolides. Differences in the structure and side groups of the lactone ring theoretically prevent cross-reactivity, allowing allergic patients to frequently tolerate other macrolides.1 Sirolimus reactions are also rare, with little known about its cross-reactivity with other macrolides. In macrolide-allergic patients who need macrolide therapy, induction of drug tolerance (desensitization procedures) is an effective option7,8 that results in immunomodulation and a temporary state of allergen-specific tolerance. Graded-dose challenge is a procedure that cautiously introduces a drug in patients who are determined to be at low risk for allergic reactions. Unlike inductions of drug tolerance, no modification of the immune response is seen in graded-dose challenges. With a successful graded-dose
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
⫹⫹ ⫹ ⫹⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ 14 18F 37F 26F 15F 23F 16F 14F 16M 4 5 6 7 8 9 10 11 12
Abbreviations: FEV1, forced expired volume in 1 second (% predicted); PC20, provocation concentration causing a 20% FEV1 fall; PetCO2, end-tidal partial pressure of CO2 (mmHg); ND, not done; NT, not tried; PIF, peak inspiratory flow. a Symptoms induced by methacholine did NOT mimic those induced by exercise.
34 35
38
ND 30 ND ND ND ND ND 32 38 ND Normal ND ND ND ND ND Normal Normal 1.3 14 ⬎16 ⬎16 8 ⬎16 4a 5a ⬎16 3.7 6.0 3.0 5.4 5.9 5.8 5.2 4.2 6.9 98 112 121 115 115 84 104 82 100 100 99 98 99 100 99 99 99 98 No No No No No No mild Cat exposure No ⫺ NT NT NT ⫺ NT NT ⫺ ⫾ ⫺ ⫺ ⫾ ⫺ ⫺ ⫺ ⫺ ⫺ ⫾
3.9 4.2 5.3 91 94 116 100 98 99 No No No ⫺ NT ⫺ ⫺ ⫾ ⫺ 15F 16F 15F 1 2 3
Ballet Track Taekwondo basketball Soccer Exercise 10 K run Exercise Swimming Exercise Track Soccer basketball Kayak
⫹ ⫹⫹ ⫹⫹
⫺ ⫺ ⫹
ICS BD
⫹ ⫹ ⫹
⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺ ⫹
36 35 37 Normal Normal Normal ⬎16 6a 12
Meth PC20 (mg/mL) PIF (L/s) FEV1 (%) Resting oxygen saturation Rhinitis Response to asthma therapy Paresthesia Presyncope (⫹) or syncope (⫹⫹) Difficulty inspiring Activity Age sex #
Table 1 Clinical characteristics and laboratory data
34 34 36
Rest
Exercise test
PetCO2
Exercise
Letters / Ann Allergy Asthma Immunol 109 (2012) 279–285
283
discussed with these patients, none admitted to pre-exercise hyperventilation, a technique believed by some to preload oxygen stores to help improve performance. Asthma was suspected in all; response to bronchodilators (n ⫽ 12) or inhaled corticosteroids (n ⫽ 6, Table 1) was absent (n ⫽ 9) or equivocal (n ⫽ 3). Rhinitis was absent except for 1 with mild perennial rhinitis and 1 with rhinitis on cat exposure. Resting oxygen saturations were uniformly high (98 –100%). Three of these patients had elevated room air oxygen saturations (98 –99%) in emergency rooms during attacks. Inspiratory and expiratory flows were normal (Table 1), and methacholine PC20 was normal (⬎8 mg/mL) in 8, and mildly (n ⫽ 1) to borderline (n ⫽ 3) reduced in 4. In 3 subjects with borderline airway hyper-responsiveness, the methacholine-induced symptoms did not mimic those that occurred with exertion. Exercise testing was done in 6; none developed EIB or hyperventilation, and symptoms were not reproduced. End-tidal partial pressure of carbon dioxide was low normal (30 –35 mmHg) and did not fall after exercise. None of the additional 11 patients was challenged with voluntary hyperventilation. We present 12 patients with non-asthmatic exercise-induced dyspnea. We suspected exercise hyperventilation but were unable to objectively confirm this in 11 of 12. The clinical clues suggesting hyperventilation include difficulty with inspiration, high resting oxygen saturation, absence of rhinitis or nocturnal symptoms, and poor response to bronchodilators. Paresthesia (n ⫽ 4) and syncope (n ⫽ 4)/presyncope (n ⫽ 8) are particularly suggestive of hyperventilation with acute respiratory alkalosis. Asthma was excluded by a normal methacholine test in most subjects, and in those who did respond to methacholine (mild or borderline) the methacholineinduced symptoms did not mimic the exercise symptoms. Possibly in this latter subset, minor bronchoconstriction might have contributed to the hyperventilation. Symptoms4,5 may be more accurate than the hyperventilation test6 in identifying hyperventilation. The gold standard for identifying exercise-induced hyperventilation would be an exercise test positive for hyperventilation with low end-tidal CO2.2 However, exercise under supervision may not reproduce symptoms or cause hyperventilation2; we suspect this may be similar to the failure to reproduce the symptom complex during practice compared with competition. Intermittent laryngeal dysfunction during exercise could produce somewhat similar symptoms,1,7 particularly difficulty with inspiration. This could not be entirely excluded in our patients. None had stridor, inspiratory flows were normal, and none developed typical attacks, stridor, or decrease in inspiratory flows during methacholine (n ⫽ 12) or exercise (n ⫽ 6) testing. However, laryngeal dysfunction can be intermittent, and normal inspiratory flow when asymptomatic does not exclude this possibility; the major diagnostic tool, fiberoptic laryngoscopy during exercise, is not routinely available. Because our subjects did not develop symptoms or inspiratory flow limitation during exercise, laryngoscopy is unlikely to have been abnormal. None of the other differential diagnoses as outlined in the EIB practice parameter7 seems plausible in these individuals. Treatment strategies include education regarding the mechanism of symptom generation secondary to hypocapnea and respiratory alkalosis and reassurance that there is no underlying organic cause of their symptoms. Breathing retraining has been suggested as a treatment for hyperventilation.8 This was attempted in 1 patient (#2) with limited success. Pharmacotherapy has limited value. In summary, we were able to identify 12 individuals suspected of exercise-induced hyperventilation. This condition, and other nonasthmatic causes of exercise limitation (eg, laryngeal dysfunction), may be more common than is generally appreciated. We recommend that clinicians dealing with asthma or exercise keep
284
Letters / Ann Allergy Asthma Immunol 109 (2012) 279–285
this possibility in mind when dealing with exercise-induced breathlessness. Mohammed AlShati, MD, FRCP(C) Donald W. Cockcroft, MD, FRCP(C) Mark E. Fenton, MD, FRCP(C) Division of Respirology Critical Care and Sleep Medicine University of Saskatchewan Saskatoon, Saskatchewan, Canada [email protected] References [1] Tilles SW. Exercise-induced respiratory symptoms: an epidemic among adolescents. Ann Allergy Asthma Immunol. 2010;104:361–367.
[2] Hammo AH, Weinberger MM. Exercise-induced hyperventilation: a psuedoasthma syndrome. Ann Allergy Asthma Immunol. 1999;82:574 –578. [3] Cockcroft DW, Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy. 1977;7:235– 243. [4] Van Dixhoorn J, Duivenvoorden HJ. Efficacy of Nijmegen questionnaire in recognition of the hyperventilation syndrome. J Psychosom Res. 1985;29:199 –206. [5] Grossman P, De Swart JCG. Diagnosis of hyperventilation syndrome on the basis of reported complaints. J Psychosom Res. 1984;28:97–104. [6] Hornsveld HK, Garssen B. Double-blind placebo-controlled study of the hyperventilation provocation test and the validity of the hyperventilation syndrome. Lancet. 1996;348:145–148. [7] Weiler JM, Anderson SA, Bonini S, et al. Pathogenesis, prevalence, diagnosis and management of exercise-induced bronchoconstriction: a practice parameter. Ann Allergy Asthma Immunol. 2010;105:S1–S47. [8] Han JN, Stegen K, De Valck C, Clement J, Van de Woestijne KP. Influence of breathing therapy on complaints, anxiety and breathing pattern in patients with hyperventilation syndrome and anxiety disorders. J Psychosom Res. 1996;41:481– 493.
Successful sirolimus graded dose challenge in an erythromycin-allergic patient Most macrolides are broad-spectrum antibiotics commonly used for the treatment of upper respiratory tract infections. Tacrolimus, sirolimus, everolimus, and temsirolimus are among the newest macrolides used for the prevention and treatment of acute rejection after solid organ transplantation and graft versus host disease after hematopoietic stem cell transplantation. Allergic reactions to macrolide antibiotics include urticaria, angioedema, anaphylaxis, Stevens-Johnson syndrome, and toxic epidermal necrolysis and are uncommon (0.4 – 3%).1 Hypersensitivity reactions to immunosuppressive macrolides are also rare, with only a few cases of sirolimus- and everolimus-associated angioedema reported.2,3 Poor understanding exists between the cross-reactivity among macrolides, especially among newer immunosuppressants; at least 1 hypersensitivity reaction has been described with use of tacrolimus in a clarithromycin-allergic patient.4 Herein, we describe a patient with erythromycin allergy who underwent successful graded dose challenge to sirolimus. A 37-year-old woman with a history of relapsed and refractory human T-lymphotropic virus-1–associated adult T cell lymphoma was admitted to the hospital for reduced-intensity human leukocyte antigen–matched sibling peripheral blood stem cell transplantation. Treatment on study protocol, NCT00074490, included a conditioning regimen of fludarabine and cyclophosphamide. Graft-versus-host disease prophylaxis consisted of sirolimus and cyclosporine, both initiated 4 days before transplantation. The patient’s medical history was significant for macrolide allergy. Two years prior, she recalled developing diffuse pruritus with the first 2 doses of a twice-daily erythromycin course prescribed for lymphadenitis; the pruritus was treated symptomatically with loratadine. One hour after the third dose, she again developed diffuse pruritus but also had urticaria, shortness of breath, and throat swelling. These symptoms resolved with administration of diphenhydramine and prednisone. Because of these symptoms, antibiotics were discontinued. Before this reaction, she had tolerated treatment with azithromycin. Nonirritating doses of erythromycin were used for evaluation 2 years after the initial reaction.5 Erythromycin was prepared using the intravenous solution. Results of skin prick test and intradermal test to erythromycin (0.05 mg/mL) were negative. Saline control was negative, and histamine (6 mg/mL) was positive, with 10-mm wheal and 40-mm flare.
Disclosures: Authors have nothing to disclose. Funding Sources: This work was supported by the Division of Intramural Research, National Institute of Allergic and Infectious Diseases and the National Cancer Institute, National Institutes of Health.
Table 1 Sirolimus oral graded dose challenge protocol Dose number
Concentration
Dose (mg)
1 2 3
1:100 1:10 1:1
0.16 1.5 14
Sirolimus oral solution 1 mg/mL was used for doses 1 and 2. Seven 2-mg oral tablets were administered simultaneously for dose 3.
Erythromycin skin testing is not validated, and a negative result does not rule out the presence of drug-specific immunoglobulin E antibodies. This patient’s reaction was consistent with a hypersensitivity reaction and therefore concerning. Because the study protocol on which she was enrolled was specifically investigating the biological and clinical effects of sirolimus, the drug could not be easily substituted. Because the cross-reactivity among macrolides is largely unknown, a graded-dose challenge was performed (Table 1). After providing informed consent, the patient orally received 1/100th of the target sirolimus loading dose (16 mg). Individual doses were administered at 30-minute intervals across 1.5 hours. No adverse reaction developed, and the patient was able to receive a total cumulative 16-mg dose of sirolimus. She began routine administration of sirolimus at the protocol-determined maintenance dose of 8 mg daily (goal level 20–30 ng/mL). She tolerated treatment without any adverse effects. Immediate reactions to macrolides are rarely reported, with diagnosis primarily relying on clinical history alone. Unfortunately, results of macrolide skin and in vitro testing often yield negative results. As shown by Seitz et al,6 only 1 patient of 125 with suspected hypersensitivity to a macrolide based on history alone tested positive to allergological testing.6 Clinical cross-reactivity among macrolides is largely unknown, with few published cases (reviewed in Seitz et al6). A large lactone ring with varying numbers of atoms is the main structural component of macrolides. Differences in the structure and side groups of the lactone ring theoretically prevent cross-reactivity, allowing allergic patients to frequently tolerate other macrolides.1 Sirolimus reactions are also rare, with little known about its cross-reactivity with other macrolides. In macrolide-allergic patients who need macrolide therapy, induction of drug tolerance (desensitization procedures) is an effective option7,8 that results in immunomodulation and a temporary state of allergen-specific tolerance. Graded-dose challenge is a procedure that cautiously introduces a drug in patients who are determined to be at low risk for allergic reactions. Unlike inductions of drug tolerance, no modification of the immune response is seen in graded-dose challenges. With a successful graded-dose