The diagnosis of asthma is usually based on typical symptoms, family history, audible wheeze, peak flow, spirometry, possibly in conjunction with atopy and blood eosinophilia, as well as response to treatment. In cases for which the diagnosis is less clear-cut, other tests may be required, including impulse oscillometry (IOS), exhaled nitric oxide fraction (FeNO) and bronchial challenge testing (figure 1)

Aaron

Brian J. Lipworth

Chapman

Galant

Manoharan

Pakhale

Sunny Jabbal

Lipworth, Brian J.

Jabbal, Sunny

Discovery Research Portal

                                                                    University of DundeeUn-diagnosing persistent adult asthmaLipworth, Brian J.; Jabbal, SunnyPublished in:European Respiratory JournalDOI:10.1183/13993003.01433-2017Publication date:2017Document VersionPeer reviewed versionLink to publication in Discovery Research PortalCitation for published version (APA):Lipworth, B. J., & Jabbal, S. (2017). Un-diagnosing persistent adult asthma. European Respiratory Journal,50(5), [1701433]. https://doi.org/10.1183/13993003.01433-2017General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 19. Apr. 2023Un-diagnosing persistent adult asthma Journal: European Respiratory Journal Manuscript ID ERJ-01433-2017.R1 Manuscript Type: Research Letter Date Submitted by the Author: 01-Aug-2017 Complete List of Authors: Jabbal, Sunny; University of Dundee, Scottish Centre for Respiratory Research Lipworth, Brian; University of Dundee, Asthma & Allergy Research Group Key Words: exhaled nitric oxide, asthma, airway hyperresponsiveness European Respiratory JournalThis is the pre-peer reviewed version of the following article: Un-diagnosing persistent adult asthma, BJ Lipworth, S Jabbal, ERJ, 1 Nov 2017 which has been published in final form at DOI:10.1183/13993003.01433-2017. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.1  Un-diagnosing persistent adult asthma 1  2 1Brian J Lipworth, 1Sunny Jabbal 3 1Scottish Centre for Respiratory Research, Ninewells Hospital & Medical School, 4 Dundee, Scotland, DD1 9SY 5  6 Correspondence to: Dr BJ Lipworth, Scottish Centre for Respiratory Research, 7 Ninewells Hospital & Medical School, University of Dundee, Dundee, DD1 9SY. 8 Tel: +44 1382 383188 b.j.lipworth@dundee.ac.uk 9  10  11  12 The diagnosis of asthma is usually based on typical symptoms , family history , 13 audible wheeze , peak flow , spirometry  , possibly in conjunction with atopy and 14 blood eosinophilia , as well as response to treatment . In cases where the 15 diagnosis is less clear cut other tests may be required including impulse 16 oscillometry (IOS), exhaled breath nitric oxide (FeNO) and bronchial challenge 17 testing (Figure).   18  19 A commonly seen pattern in our asthma clinic would be a non-smoking patient 20 presenting to primary care with an episode of viral associated persistent cough 21 and wheeze, initially unresponsive to salbutamol and antibiotic, with a normal 22 chest radiograph, negative sputum culture, normal peak flow , with or without 23 normal spirometry. Such cases may then be given empirical treatment with 24 inhaled corticosteroid (ICS) which may be continued in the longer term 25 especially if symptoms take time to resolve. This also assumes that an alternative 26 diagnosis has already been pursued in patients with persistent cough.  27  28 There is a psychological burden to an individual being diagnosed with asthma in 29 addition to the on-going costs of treatment along with the potential for ICS 30 related adverse effects. Once patients have been told they have asthma and on 31 maintenance therapy it may be difficult to persuade them that either the initial 32 diagnosis was incorrect or that they may have had an intermittent episode of 33 asthma that subsequently resolved.  34  35 Diurnal variability on serial peak flow recordings may be a useful pointer to 36 asthma but requires a motivated patient to properly perform and record 37 accurate readings. Reversibility of spirometry to inhaled salbutamol (≥15% and 38 ≥200ml increase in FEV1) is only useful for patients who have impaired FEV1 39 <80 % predicted where there is potential room for bronchodilator response. For 40 patients with a preserved FEV1 >80% predicted , or for patients who cannot 41 perform adequate spirometry ,it may be useful to consider using IOS which 42 requires less cooperation being an effort independent test carried out  during 43 normal tidal breathing  (1). A diagnosis of asthma may be supported by the 44 Page 4 of 9European Respiratory Journal1234567891011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859602  presence of heterogeneity of airway resistance as the difference between 5Hz 45 and 20Hz (R5-R20>0.07 kPa/L.s) and salbutamol reversibility ≥ 40% (2, 3). 46  47 One of the hallmarks of asthmatic  inflammation is the presence of underlying 48 airway hyper-responsiveness (AHR), as measured by bronchial challenge testing 49 using either direct (methacholine or histamine ) or indirect  ( mannitol ) acting 50 stimuli (4) . Ideally such a challenge test should be performed having first 51 stopped ICS for at least two weeks in order to avoid the possibility a false 52 negative result. Our pragmatic regimen is to half the dose of ICS every week until 53 a 200ug beclometasone equivalent dose is achieved, where upon it can be 54 stopped, followed by repeat lung function and if required a challenge test two 55 weeks later. The worsening of symptoms in association with obstructive lung 56 function at this visit upon stopping ICS may be diagnostic in itself and obviate the 57 need for performing challenge. 58  59 The dose related suppressive effects of ICS on AHR are more pronounced for 60 indirect than direct acting challenges (5, 6). Hence if a challenge test is to be 61 performed while still taking ICS, either methacholine or histamine should be 62 used rather than mannitol. The American Thoracic Society advocate a cut off 63 value for methacholine challenge as the provocative concentration to produce  a 64 20% fall in FEV1 (PC20) of ≤4mg/ml being indicative of positive AHR, whereas a 65 cut off >4≤8mg/ml is considered as being borderline (7). However, the 66 guidelines do not stipulate whether these PC20 cut offs refer to patients on or off 67 ICS. We and others recommend a pragmatic cut off value for PC20 ≤8 mg/ml for 68 direct challenge (8, 9). We also advocate measuring FeNO off ICS, the reason for 69 stopping treatment is that FeNO is maximally suppressed by low dose ICS after 70 1-2 weeks  ,while values return back to baseline after 1 week of ICS washout (10) 71 . ICS naïve patients with positive AHR (PC20 ≤8mg/ml) also have higher FeNO 72 levels than those who are AHR negative (11). In this regard an elevated FeNO ≥ 73 35 parts per billion (12) is highly predictive of persistent asthma for a patient 74 not currently using ICS . 75  76 Prior to challenge for patients taking combination inhalers the long acting beta-77 agonist (LABA) moiety should be stopped for one week while converting to ICS 78 alone followed by tapering. The additional effect of LABA and leukotriene 79 receptor antagonist (LTRA) on AHR amounts to less than one doubling dilution 80 (13, 14), so that one week off such therapy should be sufficient washout in most 81 cases. There is uncertainty about the protective effects of anti-cholinergics on 82 AHR(15-17). Long acting muscarinic antagonists should be the first drug 83 withdrawn for one week (18), prior to stopping LABA as part of sequential step 84 down therapy.  85  86 In a real life study of community diagnosed  asthma patients , there were 30 % 87 who were non responsive to both methacholine and mannitol challenges  , where 88 the median beclometasone equivalent dose was 1000ug  ,68% were  taking LABA 89 and 19% LTRA (9). In comparison to the 70% who were responders to challenge, 90 there were significant differences in values for mean FEV1 (88 vs 100%), mean 91 FeNO (26 vs 16 parts per billion), asthma control questionnaire score (1.07 vs 92 0.55) and skin prick positive response (79 vs 50%). A Canadian study found 28% 93 Page 5 of 9 European Respiratory Journal1234567891011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859603  of patients with a physician based diagnosis who had no evidence of asthma 94 when their treatment was tapered and evaluated using direct challenge testing , 95 with an estimated cost saving £2100 for each un-diagnosed patient (19). In a 96 further multicentre study from Canada using a similar protocol current asthma 97 was ruled out in 33% of cases, and after further 12 month follow up 29% 98 continued to have no evidence of asthma (8) . 99  100 Patients with a negative challenge test along with normal FeNO and IOS who 101 have persistent symptoms having stopped ICS  should then go on to have further 102 tests perhaps including upper and lower airway endoscopy , high resolution CT  103 thorax scan and gas diffusion in order  to exclude possible alternative diagnoses 104 such as chronic rhino-sinusitis , lung cancer, bronchiectasis and pulmonary 105 embolism .  106  107 Word count = 1022 108  109 Figure Legend: Flow chart for decision making in difficult cases where there may 110 be uncertainty about the diagnosis of persistent adult asthma. 111  112  113 References: 114  115  116  117 1. Galant SP, Komarow HD, Shin HW, Siddiqui S, Lipworth BJ. The case for 118 impulse oscillometry in the management of asthma in children and adults. Ann 119 Allergy Asthma Immunol. 2017;118(6):664-71. 120 2. Manoharan A, Anderson WJ, Lipworth J, Ibrahim I, Lipworth BJ. Small 121 airway dysfunction is associated with poorer asthma control.  The European 122 respiratory journal. 44. England2014. p. 1353-5. 123 3. Short PM, Anderson WJ, Manoharan A, Lipworth BJ. Usefulness of impulse 124 oscillometry for the assessment of airway hyperresponsiveness in mild-to-125 moderate adult asthma. Ann Allergy Asthma Immunol. 2015;115(1):17-20. 126 4. Chapman DG, Irvin CG. Mechanisms of airway hyper-responsiveness in 127 asthma: the past, present and yet to come. Clin Exp Allergy. 2015;45(4):706-19. 128 5. Lipworth BJ, Fowler S, Wilson A, Crompton GK, Woodcock A, Daley-Yates 129 PT. Fluticasone propionate bioavailability in asthma [1] (multiple letters). 130 Lancet. 2000;356(9242):1681-2. 131 6. Currie GP, Stenback S, Lipworth BJ. Effects of fluticasone vs. 132 fluticasone/salmeterol on airway calibre and airway hyperresponsiveness in 133 mild persistent asthma. British Journal of Clinical Pharmacology. 2003;56(1):11-134 7. 135 7. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, et al. 136 Guidelines for methacholine and exercise challenge testing-1999. This official 137 statement of the American Thoracic Society was adopted by the ATS Board of 138 Directors, July 1999. Am J Respir Crit Care Med. 2000;161(1):309-29. 139 8. Aaron SD, Vandemheen KL, FitzGerald JM, Ainslie M, Gupta S, Lemiere C, 140 et al. Reevaluation of Diagnosis in Adults With Physician-Diagnosed Asthma. 141 JAMA. 2017;317(3):269-79. 142 Page 6 of 9European Respiratory Journal1234567891011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859604  9. Manoharan A, Lipworth BJ, Craig E, Jackson C. The potential role of direct 143 and indirect bronchial challenge testing to identify overtreatment of community 144 managed asthma. Clin Exp Allergy. 2014;44(10):1240-5. 145 10. Anderson WJ, Short PM, Williamson PA, Lipworth BJ. Inhaled 146 Corticosteroid Dose Response Using Domiciliary Exhaled Nitric Oxide in 147 Persistent Asthma The FENotype Trial. Chest. 2012;142(6):1553-61. 148 11. Dupont LJ, Rochette F, Demedts MG, Verleden GM. Exhaled nitric oxide 149 correlates with airway hyperresponsiveness in steroid-naive patients with mild 150 asthma. American journal of respiratory and critical care medicine. 1998;157(3 151 Pt 1):894-8. 152 12. Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. 153 An official ATS clinical practice guideline: interpretation of exhaled nitric oxide 154 levels (FENO) for clinical applications. Am J Respir Crit Care Med. 155 2011;184(5):602-15. 156 13. Currie GP, Jackson CM, Ogston SA, Lipworth BJ. Airway-stabilizing effect 157 of long-acting beta2-agonists as add-on therapy to inhaled corticosteroids. QJM : 158 monthly journal of the Association of Physicians. 2003;96(6):435-40. 159 14. Currie GP, Lipworth BJ. Bronchoprotective effects of leukotriene receptor 160 antagonists in asthma: A meta-analysis. Chest. 2002;122(1):146-50. 161 15. Jabbal S, Manoharan A, Lipworth B. Bronchoprotective tolerance with 162 indacaterol is not modified by concomitant tiotropium in persistent asthma. Clin 163 Exp Allergy. 2017. 164 16. Britton J, Hanley SP, Garrett HV, Hadfield JW, Tattersfield AE. Dose related 165 effects of salbutamol and ipratropium bromide on airway calibre and reactivity 166 in subjects with asthma. Thorax. 1988;43(4):300-5. 167 17. Thomson NC, O'Byrne P, Hargreave FE. Prolonged asthmatic responses to 168 inhaled methacholine. The Journal of allergy and clinical immunology. 169 1983;71(4):357-62. 170 18. O'Connor BJ, Towse LJ, Barnes PJ. Prolonged effect of tiotropium bromide 171 on methacholine-induced bronchoconstriction in asthma. Am J Respir Crit Care 172 Med. 1996;154(4 Pt 1):876-80. 173 19. Pakhale S, Sumner A, Coyle D, Vandemheen K, Aaron S. (Correcting) 174 misdiagnoses of asthma: a cost effectiveness analysis. BMC Pulm Med. 175 2011;11:27. 176  177  178  179  180  181  182  183  184  185  186  187  188  189  190  191 Page 7 of 9 European Respiratory Journal1234567891011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859605   192 Page 8 of 9European Respiratory Journal123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960    Figure Legend: Flow chart for decision making in difficult cases where there may be uncertainty about the diagnosis of persistent adult asthma.   445x623mm (96 x 96 DPI)    Page 9 of 9 European Respiratory Journal123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

English

Un-diagnosing persistent adult asthma

Crossref

European Respiratory Journal

                                                                    University of DundeeUn-diagnosing persistent adult asthmaLipworth, Brian J.; Jabbal, SunnyPublished in:European Respiratory JournalDOI:10.1183/13993003.01433-2017Publication date:2017Document VersionPeer reviewed versionLink to publication in Discovery Research PortalCitation for published version (APA):Lipworth, B. J., & Jabbal, S. (2017). Un-diagnosing persistent adult asthma. European Respiratory Journal,50(5), [1701433]. https://doi.org/10.1183/13993003.01433-2017General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 19. Oct. 2019Un-diagnosing persistent adult asthma Journal: European Respiratory Journal Manuscript ID ERJ-01433-2017.R1 Manuscript Type: Research Letter Date Submitted by the Author: 01-Aug-2017 Complete List of Authors: Jabbal, Sunny; University of Dundee, Scottish Centre for Respiratory Research Lipworth, Brian; University of Dundee, Asthma & Allergy Research Group Key Words: exhaled nitric oxide, asthma, airway hyperresponsiveness European Respiratory JournalThis is the pre-peer reviewed version of the following article: Un-diagnosing persistent adult asthma, BJ Lipworth, S Jabbal, ERJ, 1 Nov 2017 which has been published in final form at DOI:10.1183/13993003.01433-2017. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.1  Un-diagnosing persistent adult asthma 1  2 1Brian J Lipworth, 1Sunny Jabbal 3 1Scottish Centre for Respiratory Research, Ninewells Hospital & Medical School, 4 Dundee, Scotland, DD1 9SY 5  6 Correspondence to: Dr BJ Lipworth, Scottish Centre for Respiratory Research, 7 Ninewells Hospital & Medical School, University of Dundee, Dundee, DD1 9SY. 8 Tel: +44 1382 383188 b.j.lipworth@dundee.ac.uk 9  10  11  12 The diagnosis of asthma is usually based on typical symptoms , family history , 13 audible wheeze , peak flow , spirometry  , possibly in conjunction with atopy and 14 blood eosinophilia , as well as response to treatment . In cases where the 15 diagnosis is less clear cut other tests may be required including impulse 16 oscillometry (IOS), exhaled breath nitric oxide (FeNO) and bronchial challenge 17 testing (Figure).   18  19 A commonly seen pattern in our asthma clinic would be a non-smoking patient 20 presenting to primary care with an episode of viral associated persistent cough 21 and wheeze, initially unresponsive to salbutamol and antibiotic, with a normal 22 chest radiograph, negative sputum culture, normal peak flow , with or without 23 normal spirometry. Such cases may then be given empirical treatment with 24 inhaled corticosteroid (ICS) which may be continued in the longer term 25 especially if symptoms take time to resolve. This also assumes that an alternative 26 diagnosis has already been pursued in patients with persistent cough.  27  28 There is a psychological burden to an individual being diagnosed with asthma in 29 addition to the on-going costs of treatment along with the potential for ICS 30 related adverse effects. Once patients have been told they have asthma and on 31 maintenance therapy it may be difficult to persuade them that either the initial 32 diagnosis was incorrect or that they may have had an intermittent episode of 33 asthma that subsequently resolved.  34  35 Diurnal variability on serial peak flow recordings may be a useful pointer to 36 asthma but requires a motivated patient to properly perform and record 37 accurate readings. Reversibility of spirometry to inhaled salbutamol (≥15% and 38 ≥200ml increase in FEV1) is only useful for patients who have impaired FEV1 39 <80 % predicted where there is potential room for bronchodilator response. For 40 patients with a preserved FEV1 >80% predicted , or for patients who cannot 41 perform adequate spirometry ,it may be useful to consider using IOS which 42 requires less cooperation being an effort independent test carried out  during 43 normal tidal breathing  (1). A diagnosis of asthma may be supported by the 44 Page 4 of 9European Respiratory Journal1234567891011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859602  presence of heterogeneity of airway resistance as the difference between 5Hz 45 and 20Hz (R5-R20>0.07 kPa/L.s) and salbutamol reversibility ≥ 40% (2, 3). 46  47 One of the hallmarks of asthmatic  inflammation is the presence of underlying 48 airway hyper-responsiveness (AHR), as measured by bronchial challenge testing 49 using either direct (methacholine or histamine ) or indirect  ( mannitol ) acting 50 stimuli (4) . Ideally such a challenge test should be performed having first 51 stopped ICS for at least two weeks in order to avoid the possibility a false 52 negative result. Our pragmatic regimen is to half the dose of ICS every week until 53 a 200ug beclometasone equivalent dose is achieved, where upon it can be 54 stopped, followed by repeat lung function and if required a challenge test two 55 weeks later. The worsening of symptoms in association with obstructive lung 56 function at this visit upon stopping ICS may be diagnostic in itself and obviate the 57 need for performing challenge. 58  59 The dose related suppressive effects of ICS on AHR are more pronounced for 60 indirect than direct acting challenges (5, 6). Hence if a challenge test is to be 61 performed while still taking ICS, either methacholine or histamine should be 62 used rather than mannitol. The American Thoracic Society advocate a cut off 63 value for methacholine challenge as the provocative concentration to produce  a 64 20% fall in FEV1 (PC20) of ≤4mg/ml being indicative of positive AHR, whereas a 65 cut off >4≤8mg/ml is considered as being borderline (7). However, the 66 guidelines do not stipulate whether these PC20 cut offs refer to patients on or off 67 ICS. We and others recommend a pragmatic cut off value for PC20 ≤8 mg/ml for 68 direct challenge (8, 9). We also advocate measuring FeNO off ICS, the reason for 69 stopping treatment is that FeNO is maximally suppressed by low dose ICS after 70 1-2 weeks  ,while values return back to baseline after 1 week of ICS washout (10) 71 . ICS naïve patients with positive AHR (PC20 ≤8mg/ml) also have higher FeNO 72 levels than those who are AHR negative (11). In this regard an elevated FeNO ≥ 73 35 parts per billion (12) is highly predictive of persistent asthma for a patient 74 not currently using ICS . 75  76 Prior to challenge for patients taking combination inhalers the long acting beta-77 agonist (LABA) moiety should be stopped for one week while converting to ICS 78 alone followed by tapering. The additional effect of LABA and leukotriene 79 receptor antagonist (LTRA) on AHR amounts to less than one doubling dilution 80 (13, 14), so that one week off such therapy should be sufficient washout in most 81 cases. There is uncertainty about the protective effects of anti-cholinergics on 82 AHR(15-17). Long acting muscarinic antagonists should be the first drug 83 withdrawn for one week (18), prior to stopping LABA as part of sequential step 84 down therapy.  85  86 In a real life study of community diagnosed  asthma patients , there were 30 % 87 who were non responsive to both methacholine and mannitol challenges  , where 88 the median beclometasone equivalent dose was 1000ug  ,68% were  taking LABA 89 and 19% LTRA (9). In comparison to the 70% who were responders to challenge, 90 there were significant differences in values for mean FEV1 (88 vs 100%), mean 91 FeNO (26 vs 16 parts per billion), asthma control questionnaire score (1.07 vs 92 0.55) and skin prick positive response (79 vs 50%). A Canadian study found 28% 93 Page 5 of 9 European Respiratory Journal1234567891011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859603  of patients with a physician based diagnosis who had no evidence of asthma 94 when their treatment was tapered and evaluated using direct challenge testing , 95 with an estimated cost saving £2100 for each un-diagnosed patient (19). In a 96 further multicentre study from Canada using a similar protocol current asthma 97 was ruled out in 33% of cases, and after further 12 month follow up 29% 98 continued to have no evidence of asthma (8) . 99  100 Patients with a negative challenge test along with normal FeNO and IOS who 101 have persistent symptoms having stopped ICS  should then go on to have further 102 tests perhaps including upper and lower airway endoscopy , high resolution CT  103 thorax scan and gas diffusion in order  to exclude possible alternative diagnoses 104 such as chronic rhino-sinusitis , lung cancer, bronchiectasis and pulmonary 105 embolism .  106  107 Word count = 1022 108  109 Figure Legend: Flow chart for decision making in difficult cases where there may 110 be uncertainty about the diagnosis of persistent adult asthma. 111  112  113 References: 114  115  116  117 1. Galant SP, Komarow HD, Shin HW, Siddiqui S, Lipworth BJ. The case for 118 impulse oscillometry in the management of asthma in children and adults. Ann 119 Allergy Asthma Immunol. 2017;118(6):664-71. 120 2. Manoharan A, Anderson WJ, Lipworth J, Ibrahim I, Lipworth BJ. Small 121 airway dysfunction is associated with poorer asthma control.  The European 122 respiratory journal. 44. England2014. p. 1353-5. 123 3. Short PM, Anderson WJ, Manoharan A, Lipworth BJ. Usefulness of impulse 124 oscillometry for the assessment of airway hyperresponsiveness in mild-to-125 moderate adult asthma. Ann Allergy Asthma Immunol. 2015;115(1):17-20. 126 4. Chapman DG, Irvin CG. Mechanisms of airway hyper-responsiveness in 127 asthma: the past, present and yet to come. Clin Exp Allergy. 2015;45(4):706-19. 128 5. Lipworth BJ, Fowler S, Wilson A, Crompton GK, Woodcock A, Daley-Yates 129 PT. Fluticasone propionate bioavailability in asthma [1] (multiple letters). 130 Lancet. 2000;356(9242):1681-2. 131 6. Currie GP, Stenback S, Lipworth BJ. Effects of fluticasone vs. 132 fluticasone/salmeterol on airway calibre and airway hyperresponsiveness in 133 mild persistent asthma. British Journal of Clinical Pharmacology. 2003;56(1):11-134 7. 135 7. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, et al. 136 Guidelines for methacholine and exercise challenge testing-1999. This official 137 statement of the American Thoracic Society was adopted by the ATS Board of 138 Directors, July 1999. Am J Respir Crit Care Med. 2000;161(1):309-29. 139 8. Aaron SD, Vandemheen KL, FitzGerald JM, Ainslie M, Gupta S, Lemiere C, 140 et al. Reevaluation of Diagnosis in Adults With Physician-Diagnosed Asthma. 141 JAMA. 2017;317(3):269-79. 142 Page 6 of 9European Respiratory Journal1234567891011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859604  9. Manoharan A, Lipworth BJ, Craig E, Jackson C. The potential role of direct 143 and indirect bronchial challenge testing to identify overtreatment of community 144 managed asthma. Clin Exp Allergy. 2014;44(10):1240-5. 145 10. Anderson WJ, Short PM, Williamson PA, Lipworth BJ. Inhaled 146 Corticosteroid Dose Response Using Domiciliary Exhaled Nitric Oxide in 147 Persistent Asthma The FENotype Trial. Chest. 2012;142(6):1553-61. 148 11. Dupont LJ, Rochette F, Demedts MG, Verleden GM. Exhaled nitric oxide 149 correlates with airway hyperresponsiveness in steroid-naive patients with mild 150 asthma. American journal of respiratory and critical care medicine. 1998;157(3 151 Pt 1):894-8. 152 12. Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. 153 An official ATS clinical practice guideline: interpretation of exhaled nitric oxide 154 levels (FENO) for clinical applications. Am J Respir Crit Care Med. 155 2011;184(5):602-15. 156 13. Currie GP, Jackson CM, Ogston SA, Lipworth BJ. Airway-stabilizing effect 157 of long-acting beta2-agonists as add-on therapy to inhaled corticosteroids. QJM : 158 monthly journal of the Association of Physicians. 2003;96(6):435-40. 159 14. Currie GP, Lipworth BJ. Bronchoprotective effects of leukotriene receptor 160 antagonists in asthma: A meta-analysis. Chest. 2002;122(1):146-50. 161 15. Jabbal S, Manoharan A, Lipworth B. Bronchoprotective tolerance with 162 indacaterol is not modified by concomitant tiotropium in persistent asthma. Clin 163 Exp Allergy. 2017. 164 16. Britton J, Hanley SP, Garrett HV, Hadfield JW, Tattersfield AE. Dose related 165 effects of salbutamol and ipratropium bromide on airway calibre and reactivity 166 in subjects with asthma. Thorax. 1988;43(4):300-5. 167 17. Thomson NC, O'Byrne P, Hargreave FE. Prolonged asthmatic responses to 168 inhaled methacholine. The Journal of allergy and clinical immunology. 169 1983;71(4):357-62. 170 18. O'Connor BJ, Towse LJ, Barnes PJ. Prolonged effect of tiotropium bromide 171 on methacholine-induced bronchoconstriction in asthma. Am J Respir Crit Care 172 Med. 1996;154(4 Pt 1):876-80. 173 19. Pakhale S, Sumner A, Coyle D, Vandemheen K, Aaron S. (Correcting) 174 misdiagnoses of asthma: a cost effectiveness analysis. BMC Pulm Med. 175 2011;11:27. 176  177  178  179  180  181  182  183  184  185  186  187  188  189  190  191 Page 7 of 9 European Respiratory Journal1234567891011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859605   192 Page 8 of 9European Respiratory Journal123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960    Figure Legend: Flow chart for decision making in difficult cases where there may be uncertainty about the diagnosis of persistent adult asthma.   445x623mm (96 x 96 DPI)    Page 9 of 9 European Respiratory Journal123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

                                                                    University of DundeeUn-diagnosing persistent adult asthmaLipworth, Brian J.; Jabbal, SunnyPublished in:European Respiratory JournalDOI:10.1183/13993003.01433-2017Publication date:2017Document VersionPeer reviewed versionLink to publication in Discovery Research PortalCitation for published version (APA):Lipworth, B. J., & Jabbal, S. (2017). Un-diagnosing persistent adult asthma. European Respiratory Journal,50(5), Article 1701433. https://doi.org/10.1183/13993003.01433-2017General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 25. Sep. 2025Un-diagnosing persistent adult asthma Journal: European Respiratory Journal Manuscript ID ERJ-01433-2017.R1 Manuscript Type: Research Letter Date Submitted by the Author: 01-Aug-2017 Complete List of Authors: Jabbal, Sunny; University of Dundee, Scottish Centre for Respiratory Research Lipworth, Brian; University of Dundee, Asthma & Allergy Research Group Key Words: exhaled nitric oxide, asthma, airway hyperresponsiveness European Respiratory JournalThis is the pre-peer reviewed version of the following article: Un-diagnosing persistent adult asthma, BJ Lipworth, S Jabbal, ERJ, 1 Nov 2017 which has been published in final form at DOI:10.1183/13993003.01433-2017. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.1  Un-diagnosing persistent adult asthma 1  2 1Brian J Lipworth, 1Sunny Jabbal 3 1Scottish Centre for Respiratory Research, Ninewells Hospital & Medical School, 4 Dundee, Scotland, DD1 9SY 5  6 Correspondence to: Dr BJ Lipworth, Scottish Centre for Respiratory Research, 7 Ninewells Hospital & Medical School, University of Dundee, Dundee, DD1 9SY. 8 Tel: +44 1382 383188 b.j.lipworth@dundee.ac.uk 9  10  11  12 The diagnosis of asthma is usually based on typical symptoms , family history , 13 audible wheeze , peak flow , spirometry  , possibly in conjunction with atopy and 14 blood eosinophilia , as well as response to treatment . In cases where the 15 diagnosis is less clear cut other tests may be required including impulse 16 oscillometry (IOS), exhaled breath nitric oxide (FeNO) and bronchial challenge 17 testing (Figure).   18  19 A commonly seen pattern in our asthma clinic would be a non-smoking patient 20 presenting to primary care with an episode of viral associated persistent cough 21 and wheeze, initially unresponsive to salbutamol and antibiotic, with a normal 22 chest radiograph, negative sputum culture, normal peak flow , with or without 23 normal spirometry. Such cases may then be given empirical treatment with 24 inhaled corticosteroid (ICS) which may be continued in the longer term 25 especially if symptoms take time to resolve. This also assumes that an alternative 26 diagnosis has already been pursued in patients with persistent cough.  27  28 There is a psychological burden to an individual being diagnosed with asthma in 29 addition to the on-going costs of treatment along with the potential for ICS 30 related adverse effects. Once patients have been told they have asthma and on 31 maintenance therapy it may be difficult to persuade them that either the initial 32 diagnosis was incorrect or that they may have had an intermittent episode of 33 asthma that subsequently resolved.  34  35 Diurnal variability on serial peak flow recordings may be a useful pointer to 36 asthma but requires a motivated patient to properly perform and record 37 accurate readings. Reversibility of spirometry to inhaled salbutamol (≥15% and 38 ≥200ml increase in FEV1) is only useful for patients who have impaired FEV1 39 <80 % predicted where there is potential room for bronchodilator response. For 40 patients with a preserved FEV1 >80% predicted , or for patients who cannot 41 perform adequate spirometry ,it may be useful to consider using IOS which 42 requires less cooperation being an effort independent test carried out  during 43 normal tidal breathing  (1). A diagnosis of asthma may be supported by the 44 Page 4 of 9European Respiratory Journal1234567891011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859602  presence of heterogeneity of airway resistance as the difference between 5Hz 45 and 20Hz (R5-R20>0.07 kPa/L.s) and salbutamol reversibility ≥ 40% (2, 3). 46  47 One of the hallmarks of asthmatic  inflammation is the presence of underlying 48 airway hyper-responsiveness (AHR), as measured by bronchial challenge testing 49 using either direct (methacholine or histamine ) or indirect  ( mannitol ) acting 50 stimuli (4) . Ideally such a challenge test should be performed having first 51 stopped ICS for at least two weeks in order to avoid the possibility a false 52 negative result. Our pragmatic regimen is to half the dose of ICS every week until 53 a 200ug beclometasone equivalent dose is achieved, where upon it can be 54 stopped, followed by repeat lung function and if required a challenge test two 55 weeks later. The worsening of symptoms in association with obstructive lung 56 function at this visit upon stopping ICS may be diagnostic in itself and obviate the 57 need for performing challenge. 58  59 The dose related suppressive effects of ICS on AHR are more pronounced for 60 indirect than direct acting challenges (5, 6). Hence if a challenge test is to be 61 performed while still taking ICS, either methacholine or histamine should be 62 used rather than mannitol. The American Thoracic Society advocate a cut off 63 value for methacholine challenge as the provocative concentration to produce  a 64 20% fall in FEV1 (PC20) of ≤4mg/ml being indicative of positive AHR, whereas a 65 cut off >4≤8mg/ml is considered as being borderline (7). However, the 66 guidelines do not stipulate whether these PC20 cut offs refer to patients on or off 67 ICS. We and others recommend a pragmatic cut off value for PC20 ≤8 mg/ml for 68 direct challenge (8, 9). We also advocate measuring FeNO off ICS, the reason for 69 stopping treatment is that FeNO is maximally suppressed by low dose ICS after 70 1-2 weeks  ,while values return back to baseline after 1 week of ICS washout (10) 71 . ICS naïve patients with positive AHR (PC20 ≤8mg/ml) also have higher FeNO 72 levels than those who are AHR negative (11). In this regard an elevated FeNO ≥ 73 35 parts per billion (12) is highly predictive of persistent asthma for a patient 74 not currently using ICS . 75  76 Prior to challenge for patients taking combination inhalers the long acting beta-77 agonist (LABA) moiety should be stopped for one week while converting to ICS 78 alone followed by tapering. The additional effect of LABA and leukotriene 79 receptor antagonist (LTRA) on AHR amounts to less than one doubling dilution 80 (13, 14), so that one week off such therapy should be sufficient washout in most 81 cases. There is uncertainty about the protective effects of anti-cholinergics on 82 AHR(15-17). Long acting muscarinic antagonists should be the first drug 83 withdrawn for one week (18), prior to stopping LABA as part of sequential step 84 down therapy.  85  86 In a real life study of community diagnosed  asthma patients , there were 30 % 87 who were non responsive to both methacholine and mannitol challenges  , where 88 the median beclometasone equivalent dose was 1000ug  ,68% were  taking LABA 89 and 19% LTRA (9). In comparison to the 70% who were responders to challenge, 90 there were significant differences in values for mean FEV1 (88 vs 100%), mean 91 FeNO (26 vs 16 parts per billion), asthma control questionnaire score (1.07 vs 92 0.55) and skin prick positive response (79 vs 50%). A Canadian study found 28% 93 Page 5 of 9 European Respiratory Journal1234567891011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859603  of patients with a physician based diagnosis who had no evidence of asthma 94 when their treatment was tapered and evaluated using direct challenge testing , 95 with an estimated cost saving £2100 for each un-diagnosed patient (19). In a 96 further multicentre study from Canada using a similar protocol current asthma 97 was ruled out in 33% of cases, and after further 12 month follow up 29% 98 continued to have no evidence of asthma (8) . 99  100 Patients with a negative challenge test along with normal FeNO and IOS who 101 have persistent symptoms having stopped ICS  should then go on to have further 102 tests perhaps including upper and lower airway endoscopy , high resolution CT  103 thorax scan and gas diffusion in order  to exclude possible alternative diagnoses 104 such as chronic rhino-sinusitis , lung cancer, bronchiectasis and pulmonary 105 embolism .  106  107 Word count = 1022 108  109 Figure Legend: Flow chart for decision making in difficult cases where there may 110 be uncertainty about the diagnosis of persistent adult asthma. 111  112  113 References: 114  115  116  117 1. Galant SP, Komarow HD, Shin HW, Siddiqui S, Lipworth BJ. 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The potential role of direct 143 and indirect bronchial challenge testing to identify overtreatment of community 144 managed asthma. Clin Exp Allergy. 2014;44(10):1240-5. 145 10. Anderson WJ, Short PM, Williamson PA, Lipworth BJ. Inhaled 146 Corticosteroid Dose Response Using Domiciliary Exhaled Nitric Oxide in 147 Persistent Asthma The FENotype Trial. Chest. 2012;142(6):1553-61. 148 11. Dupont LJ, Rochette F, Demedts MG, Verleden GM. Exhaled nitric oxide 149 correlates with airway hyperresponsiveness in steroid-naive patients with mild 150 asthma. American journal of respiratory and critical care medicine. 1998;157(3 151 Pt 1):894-8. 152 12. Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. 153 An official ATS clinical practice guideline: interpretation of exhaled nitric oxide 154 levels (FENO) for clinical applications. Am J Respir Crit Care Med. 155 2011;184(5):602-15. 156 13. Currie GP, Jackson CM, Ogston SA, Lipworth BJ. 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BMC Pulm Med. 175 2011;11:27. 176  177  178  179  180  181  182  183  184  185  186  187  188  189  190  191 Page 7 of 9 European Respiratory Journal1234567891011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859605   192 Page 8 of 9European Respiratory Journal123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960    Figure Legend: Flow chart for decision making in difficult cases where there may be uncertainty about the diagnosis of persistent adult asthma.   445x623mm (96 x 96 DPI)    Page 9 of 9 European Respiratory Journal123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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Un-diagnosing persistent adult asthma

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