- Email: [email protected]
The neural underpinnings of asthma
254 Correspondence
J ALLERGY CLIN IMMUNOL JANUARY 2007
FIG 1. Changes in submucosal eosinophil counts for 100/50 mg of FP/salmeterol and 250 mg of FP. Red bars denote median at baseline and at end point.
From athe University of Wisconsin, Madison Wis; bGlaxoSmithKline, Research Triangle Park, NC; and cSouthampton General Hospital, Southampton, United Kingdom. E-mail: [email protected]. Disclosure of potential conflict of interest: N. N. Jarjour has consultant arrangements with Asthmatx, Inc; has received grant support from GlaxoSmithKline, Aventis, and Dey Pharmaceuticals; and is on the speakers’ bureau for Schering-Plough. P. M. Dorinsky is employed by GlaxoSmithKline. R. Djukanovic has received grant support from GlaxoSmithKline.
REFERENCES 1. D’Urzo TD. Control of airway inflammation. J Allergy Clin Immunol 2007;119:252-3. 2. Djukanovic R, Wilson JW, Britten KM, Wison SJ, Walls AF, Roche WR, et al. Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis 1992;145:669-74. Available online November 6, 2006. doi:10.1016/j.jaci.2006.09.033
The neural underpinnings of asthma To the Editor: We read with interest the review article by Cockroft and Davis1 on the ‘‘Mechanisms of airway hyperresponsiveness’’ in asthma. The authors suggest that airway hyperresponsiveness (AHR) in asthma is primarily related to the influx of inflammatory cells (‘‘inducible AHR’’) and abnormalities of the smooth muscle and the subepithelial matrix (‘‘persistent AHR’’). Dysfunction of airway nerves as a contributory cause of AHR in asthma is dismissed as a ‘‘historical’’ point of view that lacks evidence.1 This statement is unsubstantiated. There is now growing evidence that AHR in asthma is at least in part related to a local overexpression of neuronal mediators such as neurotrophins that induce a hyperreactivity of nerves innervating the airways.2 Of note, it is demonstrated in the same issue of the
Correspondence 255
J ALLERGY CLIN IMMUNOL VOLUME 119, NUMBER 1
Journal that neurotrophin receptor antagonists might be of therapeutic value to reduce neuronal hyperreactivity in allergic asthma.3 This neuronal hyperreactivity is both ‘‘inducible’’ (because infiltrating immune cells produce neurotrophins) and ‘‘persistent’’ (because neuronal function can be altered for several weeks or months after neurotrophin exposure), and may therefore not fit into the dichotomous model postulated in the review. Although AHR is a characteristic feature in patients with asthma, it becomes increasingly clear that the pathways leading to this AHR are very heterogenous and complex in nature. This is reflected by the fact that patients with asthma display an individual pattern of hyperresponsiveness to stimuli such as methacholine, histamine, or AMP.1 Some of these stimuli (such as histamine) act not only on smooth muscle cells but also on neurons and may therefore reflect in part neuronal dysfunction in asthma.2 Thus, there are clues from clinical practice as well as from the current literature indicating that neuronal dysfunction contributes to AHR in asthma. These clues should be included in a comprehensive and up-to-date review. Marek Lommatzsch, MD J. Christian Virchow, MD, FRCP, FCCP, FAAAAI From the Department of Pneumology, University of Rostock, Rostock, Germany. E-mail: [email protected]. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.
REFERENCES 1. Cockcroft DW, Davis BE. Mechanisms of airway hyperresponsiveness. J Allergy Clin Immunol 2006;118:551-9. 2. Lommatzsch M, Schloetcke K, Klotz J, Schuhbaeck K, Zingler D, Zingler C, et al. Brain-derived neurotrophic factor in platelets and airflow limitation in asthma. Am J Respir Crit Care Med 2005;171:115-20. 3. Nassenstein C, Dawbarn D, Pollock K, Allen SJ, Erpenbeck VJ, Spies E, et al. Pulmonary distribution, regulation, and functional role of Trk receptors in a murine model of asthma. J Allergy Clin Immunol 2006;118: 597-605. Available online November 29, 2006. doi:10.1016/j.jaci.2006.10.004
Reply To the Editor: We thank Drs Lommatzsch and Virchow1 for their interest in our recent review.2 The data presented in their recent publications are both novel and potentially important. We apologize for overlooking their first publication. There is no doubt that the mechanisms of airway hyperresponsiveness are both complex and multiple. We agree that (potentially inducible) local involvement of neuronal regulation may play a modulating role in airway responsiveness. However, it still seems unlikely to us that primary (central) neurologic abnormalities, such as those raised in our review for historical interest, are likely to be important as causes of airway hyperresponsiveness. We look forward with interest to further research in this important area.
Donald W. Cockcroft, MD, FRCP(C) Beth E. Davis, BSc From the Department of Medicine, Division of Respirology, Critical Care and Sleep Medicine, Royal University Hospital/University of Saskatchewan, Saskatoon, Saskatchewan, Canada. E-mail: [email protected]. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.
REFERENCES 1. Lommatzsch M, Virchow JC. The neural underpinnings of asthma. J Allergy Clin Immunol 2007;119:254-5. 2. Cockcroft DW, Davis BE. Mechanisms of airway hyperresponsiveness. J Allergy Clin Immunol 2006;118:551-9. Available online November 29, 2006. doi:10.1016/j.jaci.2006.10.003
In response to dosing omalizumab in allergic asthma To the Editor: In a recent letter to the Editor (March 2006), Rambasek and Kavuru1 raised an issue related to omalizumab (Xolair, Novartis Pharmaceuticals, East Hanover, NJ) dosing. In the letter, the authors highlighted that dosing requirements, and consequently hypothetical costs, may differ depending on whether the dose is individualized using a published formula (weight 3 IgE 3 0.016) or according to a ‘‘pocket card’’ (dosing table) used in clinical trials. Pharmacodynamic modeling of phase I/II studies indicated that dosing of omalizumab should be at least 0.016 mg/kg/(IU/mL) every 4 weeks to reduce serum IgE concentrations optimally. This projected minimum dose requirement, together with the need for simplified dosing, led to the development of a tiered dosing table (Fig 1). Furthermore, the dosing table reduces the potential risk of any miscalculations that could lead to dosing errors. The efficacy and safety of omalizumab were demonstrated prospectively in phase III clinical trials,2-4 which subsequently led to Food and Drug Administration approval of omalizumab and inclusion of the accompanying dosing table in the US product label. Serum IgE concentrations were reduced to less than 25 IU/mL in 95% of the patients in the pivotal trials. In other words, the efficacy and safety of omalizumab when dosed according to the dosing table has been prospectively validated in well controlled trials.2-4 In contrast, we do not have data that would support individualized dosing according to the 0.016 mg/kg/(IU/mL) multiplier. An additional concern related to omalizumab dosing is the restriction to patients with a pretreatment total IgE of >30 to 700 IU/mL. At present, there are no data to support a recommendation for omalizumab use in patients with IgE-mediated (allergic) asthma with levels outside this range. However, studies are being considered to investigate the efficacy and safety of omalizumab in patients with pretreatment total IgE levels >700 IU/mL.
J ALLERGY CLIN IMMUNOL JANUARY 2007
FIG 1. Changes in submucosal eosinophil counts for 100/50 mg of FP/salmeterol and 250 mg of FP. Red bars denote median at baseline and at end point.
From athe University of Wisconsin, Madison Wis; bGlaxoSmithKline, Research Triangle Park, NC; and cSouthampton General Hospital, Southampton, United Kingdom. E-mail: [email protected]. Disclosure of potential conflict of interest: N. N. Jarjour has consultant arrangements with Asthmatx, Inc; has received grant support from GlaxoSmithKline, Aventis, and Dey Pharmaceuticals; and is on the speakers’ bureau for Schering-Plough. P. M. Dorinsky is employed by GlaxoSmithKline. R. Djukanovic has received grant support from GlaxoSmithKline.
REFERENCES 1. D’Urzo TD. Control of airway inflammation. J Allergy Clin Immunol 2007;119:252-3. 2. Djukanovic R, Wilson JW, Britten KM, Wison SJ, Walls AF, Roche WR, et al. Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis 1992;145:669-74. Available online November 6, 2006. doi:10.1016/j.jaci.2006.09.033
The neural underpinnings of asthma To the Editor: We read with interest the review article by Cockroft and Davis1 on the ‘‘Mechanisms of airway hyperresponsiveness’’ in asthma. The authors suggest that airway hyperresponsiveness (AHR) in asthma is primarily related to the influx of inflammatory cells (‘‘inducible AHR’’) and abnormalities of the smooth muscle and the subepithelial matrix (‘‘persistent AHR’’). Dysfunction of airway nerves as a contributory cause of AHR in asthma is dismissed as a ‘‘historical’’ point of view that lacks evidence.1 This statement is unsubstantiated. There is now growing evidence that AHR in asthma is at least in part related to a local overexpression of neuronal mediators such as neurotrophins that induce a hyperreactivity of nerves innervating the airways.2 Of note, it is demonstrated in the same issue of the
Correspondence 255
J ALLERGY CLIN IMMUNOL VOLUME 119, NUMBER 1
Journal that neurotrophin receptor antagonists might be of therapeutic value to reduce neuronal hyperreactivity in allergic asthma.3 This neuronal hyperreactivity is both ‘‘inducible’’ (because infiltrating immune cells produce neurotrophins) and ‘‘persistent’’ (because neuronal function can be altered for several weeks or months after neurotrophin exposure), and may therefore not fit into the dichotomous model postulated in the review. Although AHR is a characteristic feature in patients with asthma, it becomes increasingly clear that the pathways leading to this AHR are very heterogenous and complex in nature. This is reflected by the fact that patients with asthma display an individual pattern of hyperresponsiveness to stimuli such as methacholine, histamine, or AMP.1 Some of these stimuli (such as histamine) act not only on smooth muscle cells but also on neurons and may therefore reflect in part neuronal dysfunction in asthma.2 Thus, there are clues from clinical practice as well as from the current literature indicating that neuronal dysfunction contributes to AHR in asthma. These clues should be included in a comprehensive and up-to-date review. Marek Lommatzsch, MD J. Christian Virchow, MD, FRCP, FCCP, FAAAAI From the Department of Pneumology, University of Rostock, Rostock, Germany. E-mail: [email protected]. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.
REFERENCES 1. Cockcroft DW, Davis BE. Mechanisms of airway hyperresponsiveness. J Allergy Clin Immunol 2006;118:551-9. 2. Lommatzsch M, Schloetcke K, Klotz J, Schuhbaeck K, Zingler D, Zingler C, et al. Brain-derived neurotrophic factor in platelets and airflow limitation in asthma. Am J Respir Crit Care Med 2005;171:115-20. 3. Nassenstein C, Dawbarn D, Pollock K, Allen SJ, Erpenbeck VJ, Spies E, et al. Pulmonary distribution, regulation, and functional role of Trk receptors in a murine model of asthma. J Allergy Clin Immunol 2006;118: 597-605. Available online November 29, 2006. doi:10.1016/j.jaci.2006.10.004
Reply To the Editor: We thank Drs Lommatzsch and Virchow1 for their interest in our recent review.2 The data presented in their recent publications are both novel and potentially important. We apologize for overlooking their first publication. There is no doubt that the mechanisms of airway hyperresponsiveness are both complex and multiple. We agree that (potentially inducible) local involvement of neuronal regulation may play a modulating role in airway responsiveness. However, it still seems unlikely to us that primary (central) neurologic abnormalities, such as those raised in our review for historical interest, are likely to be important as causes of airway hyperresponsiveness. We look forward with interest to further research in this important area.
Donald W. Cockcroft, MD, FRCP(C) Beth E. Davis, BSc From the Department of Medicine, Division of Respirology, Critical Care and Sleep Medicine, Royal University Hospital/University of Saskatchewan, Saskatoon, Saskatchewan, Canada. E-mail: [email protected]. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.
REFERENCES 1. Lommatzsch M, Virchow JC. The neural underpinnings of asthma. J Allergy Clin Immunol 2007;119:254-5. 2. Cockcroft DW, Davis BE. Mechanisms of airway hyperresponsiveness. J Allergy Clin Immunol 2006;118:551-9. Available online November 29, 2006. doi:10.1016/j.jaci.2006.10.003
In response to dosing omalizumab in allergic asthma To the Editor: In a recent letter to the Editor (March 2006), Rambasek and Kavuru1 raised an issue related to omalizumab (Xolair, Novartis Pharmaceuticals, East Hanover, NJ) dosing. In the letter, the authors highlighted that dosing requirements, and consequently hypothetical costs, may differ depending on whether the dose is individualized using a published formula (weight 3 IgE 3 0.016) or according to a ‘‘pocket card’’ (dosing table) used in clinical trials. Pharmacodynamic modeling of phase I/II studies indicated that dosing of omalizumab should be at least 0.016 mg/kg/(IU/mL) every 4 weeks to reduce serum IgE concentrations optimally. This projected minimum dose requirement, together with the need for simplified dosing, led to the development of a tiered dosing table (Fig 1). Furthermore, the dosing table reduces the potential risk of any miscalculations that could lead to dosing errors. The efficacy and safety of omalizumab were demonstrated prospectively in phase III clinical trials,2-4 which subsequently led to Food and Drug Administration approval of omalizumab and inclusion of the accompanying dosing table in the US product label. Serum IgE concentrations were reduced to less than 25 IU/mL in 95% of the patients in the pivotal trials. In other words, the efficacy and safety of omalizumab when dosed according to the dosing table has been prospectively validated in well controlled trials.2-4 In contrast, we do not have data that would support individualized dosing according to the 0.016 mg/kg/(IU/mL) multiplier. An additional concern related to omalizumab dosing is the restriction to patients with a pretreatment total IgE of >30 to 700 IU/mL. At present, there are no data to support a recommendation for omalizumab use in patients with IgE-mediated (allergic) asthma with levels outside this range. However, studies are being considered to investigate the efficacy and safety of omalizumab in patients with pretreatment total IgE levels >700 IU/mL.