Inhaled allergen bronchoprovocation tests
2013; Elsevier BV; Volume: 132; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2013.08.023
ISSN1097-6825
AutoresZuzana Diamant, Gail M. Gauvreau, D COCKCROFT, Louis‐Philippe Boulet, Peter Sterk, Frans H. de Jongh, Barbro Dahlén, Paul M. O’Byrne,
Tópico(s)Respiratory and Cough-Related Research
ResumoThe allergen bronchoprovocation test is a long-standing exacerbation model of allergic asthma that can induce several clinical and pathophysiologic features of asthma in sensitized subjects. Standardized allergen challenge is primarily a research tool, and when properly conducted by qualified and experienced investigators, it is safe and highly reproducible. In combination with validated airway sampling and sensitive detection techniques, allergen challenge allows the study of several features of the physiology of mainly TH2 cell–driven asthma in relation to the kinetics of the underlying airway pathology occurring during the allergen-induced late response. Furthermore, given the small within-subject variability in allergen-induced airway responses, allergen challenge offers an adequate disease model for the evaluation of new (targeted) controller therapies for asthma in a limited number of subjects. In proof-of-efficacy studies thus far, allergen challenge showed a fair positive predicted value and an excellent negative predictive value for the actual clinical efficacy of new antiasthma therapies, underscoring its important role in early drug development. In this review we provide recommendations on challenge methods, response measurements, sample size, safety, and harmonization for future applications. The allergen bronchoprovocation test is a long-standing exacerbation model of allergic asthma that can induce several clinical and pathophysiologic features of asthma in sensitized subjects. Standardized allergen challenge is primarily a research tool, and when properly conducted by qualified and experienced investigators, it is safe and highly reproducible. In combination with validated airway sampling and sensitive detection techniques, allergen challenge allows the study of several features of the physiology of mainly TH2 cell–driven asthma in relation to the kinetics of the underlying airway pathology occurring during the allergen-induced late response. Furthermore, given the small within-subject variability in allergen-induced airway responses, allergen challenge offers an adequate disease model for the evaluation of new (targeted) controller therapies for asthma in a limited number of subjects. In proof-of-efficacy studies thus far, allergen challenge showed a fair positive predicted value and an excellent negative predictive value for the actual clinical efficacy of new antiasthma therapies, underscoring its important role in early drug development. In this review we provide recommendations on challenge methods, response measurements, sample size, safety, and harmonization for future applications. Asthma and allergy are interrelated disorders with an increasing prevalence worldwide.1Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, 2012. Available at: http://www.ginasthma.org/. Accessed March 31, 2013.Google Scholar, 2Bousquet J. Khaltaev N. Cruz A.A. Denburg J. Fokkens W.J. Togias A. et al.Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).Allergy. 2008; 63: 8-160Crossref PubMed Scopus (1406) Google Scholar In sensitized asthmatic patients exposure to relevant allergens induces the development and persistence of airway inflammation.3O’Byrne P.M. Gauvreau G.M. Brannan J.D. Provoked models of asthma: what have we learnt?.Clin Exp Allergy. 2009; 39: 181-192Crossref PubMed Scopus (43) Google Scholar These sequelae are known to be associated with airway hyperresponsiveness (AHR) to nonspecific triggers and loss of asthma control.4Cockcroft D.W. Mechanism of perennial allergic asthma.Lancet. 1983; 2: 253-256Abstract PubMed Google Scholar For almost 3 decades, standardized allergen bronchoprovocation testing or allergen challenge has served as a validated model mimicking the acute and some of the more chronic features of asthma in human subjects,5Cockcroft D.W. Murdock K.Y. Kirby J. Hargreave F. Prediction of airway responsiveness to allergen from skin sensitivity to allergen and airway responsiveness to histamine.Am Rev Respir Dis. 1987; 135: 264-267PubMed Google Scholar, 6Cockcroft D.W. Murdock K.Y. Changes in bronchial responsiveness to histamine at intervals after allergen challenge.Thorax. 1987; 42: 302-308Crossref PubMed Google Scholar which might differ in several aspects from animal allergen challenge models.7Wenzel S.E. Holgate S.T. The mouse trap: It still yields few answers in asthma.Am J Respir Crit Care Med. 2006; 174: 1173-1176Crossref PubMed Scopus (79) Google Scholar, 8Lommatzsch M. Julius P. Kuepper M. Garn H. Bratke K. Irmscher S. et al.The course of allergen-induced leukocyte infiltration in human and experimental asthma.J Allergy Clin Immunol. 2006; 118: 91-97Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar In research settings allergen challenge permits the study of various features of TH2 cell–driven asthma and the evaluation of (targeted) asthma therapies.9Gauvreau G.M. Watson R.M. O’Byrne P.M. Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation.Am J Respir Crit Care Med. 1999; 160: 640-647Crossref PubMed Google Scholar, 10Cockcroft D.W. Hargreave F.E. O'Byrne P.M. Boulet L.P. Understanding allergic asthma from allergen inhalation tests.Can Respir J. 2007; 14: 414-418PubMed Google Scholar, 11Boulet L.P. Gauvreau G. Boulay M.E. O'Byrne P. Cockcroft D.W. Clinical Investigative Collaboration, Canadian Network of Centers of Excellence AllerGen. The allergen bronchoprovocation model: an important tool for the investigation of new asthma anti-inflammatory therapies.Allergy. 2007; 62: 1101-1110Crossref PubMed Scopus (27) Google Scholar, 12O’Byrne P.M. Allergen-induced airway inflammation and its therapeutic intervention.Allergy Asthma Immunol Res. 2009; 1: 3-9Crossref PubMed Scopus (17) Google Scholar Specific allergen challenge is routinely used in the investigation of occupational sensitization but otherwise is primarily a research tool that should only be conducted in specialized centers with demonstrable expertise and experience with this clinical model. More recently, standardization and optimization of noninvasive airway sampling techniques and several biomarker detection methods have added to the interest in this specific asthma model.13Diamant Z. Boot J.D. Kamerling I. Bjermer L. Methods used in clinical development of novel anti-asthma therapies.Respir Med. 2008; 102: 332-338Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar This has driven the development of various challenge methods conducted in clinical research settings both inside and outside the hospital environment.14Taylor D.A. Harris J.G. O'Connor B.J. Comparison of incremental and bolus dose inhaled allergen challenge in asthmatic patients.Clin Exp Allergy. 2000; 30: 56-63Crossref PubMed Scopus (18) Google Scholar, 15Ihre E. Zetterström O. Increase in non-specific bronchial responsiveness after repeated inhalation of low doses of allergen.Clin Exp Allergy. 1993; 23: 298-305Crossref PubMed Google Scholar Unlike provocation tests with direct bronchoconstrictors, such as methacholine and histamine, which produce short-lived transient bronchospasm through direct interaction with receptors on airway smooth muscle, allergen challenge is an indirect test inducing prolonged bronchoconstriction through the release of proinflammatory mediators (Fig 1).3O’Byrne P.M. Gauvreau G.M. Brannan J.D. Provoked models of asthma: what have we learnt?.Clin Exp Allergy. 2009; 39: 181-192Crossref PubMed Scopus (43) Google Scholar In sensitized subjects inhalation of a provocative dose of a relevant allergen is known to produce acute bronchoconstriction (ie, the early asthmatic response [EAR]), which in approximately 50% of cases is followed by an LAR. The LAR is characterized by an inflammatory airway response, prolonged airway narrowing, and AHR that can last for days to weeks (see Fig E1, Fig E2 in this article's Online Repository at www.jacionline.org).3O’Byrne P.M. Gauvreau G.M. Brannan J.D. Provoked models of asthma: what have we learnt?.Clin Exp Allergy. 2009; 39: 181-192Crossref PubMed Scopus (43) Google Scholar, 4Cockcroft D.W. Mechanism of perennial allergic asthma.Lancet. 1983; 2: 253-256Abstract PubMed Google Scholar, 9Gauvreau G.M. Watson R.M. O’Byrne P.M. Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation.Am J Respir Crit Care Med. 1999; 160: 640-647Crossref PubMed Google Scholar Therefore inhaled allergen challenge involves more complex procedures and requires more onsite expertise than just a well-written standard operating procedure (SOP) for safe and reproducible conduct. Presently, there are 3 types of allergen challenges that can be applied within the respiratory tract: (1) nasal challenge, (2) segmental lung challenge, and (3) total lung or inhaled challenge. The latter includes incremental and bolus (ie, high-dose) allergen challenges,5Cockcroft D.W. Murdock K.Y. Kirby J. Hargreave F. Prediction of airway responsiveness to allergen from skin sensitivity to allergen and airway responsiveness to histamine.Am Rev Respir Dis. 1987; 135: 264-267PubMed Google Scholar, 14Taylor D.A. Harris J.G. O'Connor B.J. Comparison of incremental and bolus dose inhaled allergen challenge in asthmatic patients.Clin Exp Allergy. 2000; 30: 56-63Crossref PubMed Scopus (18) Google Scholar repeated low-dose allergen challenge,15Ihre E. Zetterström O. Increase in non-specific bronchial responsiveness after repeated inhalation of low doses of allergen.Clin Exp Allergy. 1993; 23: 298-305Crossref PubMed Google Scholar and “real-life” allergen exposure rooms.16Devillier P. Le Gall M. Horak F. The allergen challenge chamber: a valuable tool for optimizing the clinical development of pollen immunotherapy.Allergy. 2011; 66: 163-169Crossref PubMed Scopus (13) Google Scholar Despite similarities across the methodologies17Frølund L. Svendsen U.G. Nielsen N.H. Weeke B. Madsen F. Bronchial allergen challenge: comparison between two different methods of provocation.Clin Allergy. 1987; 17: 439-448Crossref PubMed Google Scholar and airway compartments,2Bousquet J. Khaltaev N. Cruz A.A. Denburg J. Fokkens W.J. Togias A. et al.Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).Allergy. 2008; 63: 8-160Crossref PubMed Scopus (1406) Google Scholar the methods are not interchangeable because each challenge addresses different inflammatory pathways, pathophysiologic pathways, or both. This review focuses on methodological aspects, safety, and the main applications of the inhaled allergen challenge. Because allergen challenge is increasingly applied in different research settings, it is important to optimize the safety of the methods used, as well as the comparability of data across study centers. Historical background on allergen bronchoprovocation is provided in the text in this article's Online Repository at www.jacionline.org. Although generally well-tolerated, occasionally, inhaled allergen challenge can induce severe (acute) bronchoconstriction or even generalized anaphylaxis, requiring urgent medical intervention. Therefore, and in agreement with good clinical practice, allergen bronchoprovocation tests should only be performed in centers with demonstrable expertise and ample experience with the required methodologies and subject populations.18Sterk P.J. Fabbri L.M. Quanjer P.H. Cockcroft D.W. O'Byrne P.M. Anderson S.D. et al.Airway responsiveness. Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Report of the Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society.Eur Respir J (Suppl). 1993; 16: 53-83Crossref PubMed Google Scholar In any center undertaking inhaled allergen challenge, adequate knowledge of the pathophysiology and management of asthma should be in place. These training aspects should be obvious from updated curriculum vitae; training records, training certificates, or both; and/or publications. Apart from dedicated research staff, there should always be immediate access to an experienced (pulmonary) physician with demonstrable knowledge of asthma who is capable of managing acute bronchoconstriction and anaphylaxis. This physician should always be aware that a challenge is being conducted and be present during or in close vicinity to the actual challenge. All members of the team should be trained in resuscitation methods, and an updated crash cart should be close at hand, along with clearly written SOPs for anaphylaxis and acute bronchoconstriction management, including the emergency telephone number of the hospital. The contents of the crash cart should include cardiopulmonary resuscitation equipment, intravenous fluids (including a plasma expander and normal saline), adrenalin, antihistamines, and corticosteroids for parenteral use, along with sterile injection fluid (NaCl 0.9%), inhaled and intravenous bronchodilators (both short-acting β2-agonists and anticholinergics), a nebulizing device, a ready-to-use oxygen source and mask, needles, and syringes. The subject should never be left unattended during or after the challenge procedure, and FEV1 should be closely monitored for at least 7 hours after challenge. After the last FEV1 measurement (≥7 hours after challenge), subjects should receive inhaled bronchodilators until the FEV1 returns to within approximately 10% of the preallergen baseline value. Once this is achieved and the subject is clinically stable, subject can be sent home and provided with the following:•transportation from the research center to his or her home address, preferably without being left home alone;•a bronchodilator (preferably a metered-dose inhaler in combination with an aerochamber) and an oral corticosteroid, including instructions on use;•clear (both oral and written) instructions on the possibility of postchallenge recurrence of bronchoconstriction and its management with inhaled bronchodilator use; and•emergency contact information of the on-call qualified physician who has been notified about the subject. To prevent sensitization, bronchoconstriction, or both in susceptible investigators, an exhaust hood, high-efficiency particulate air (HEPA) filters, or both should be used during allergen nebulization, and the room should be adequately ventilated after the procedure. Other good clinical practice–based prerequisites relating to safety and data quality and integrity are as follows:•close vicinity to a hospital with an operational intensive care unit;•adequate, well-ventilated challenge rooms with standardized humidity conditions within an irritant-free and (tobacco) smoke-free area;•regularly calibrated and serviced equipment meeting American Thoracic Society/European Respiratory Society criteria;•standardized validated SOPs;•adequate databases; and•a qualified laboratory and pharmacy complying with locally required standards. In a multicenter setting ample attention should be paid to prior harmonization of the SOPs and equipment across the participating centers. Well-defined subject inclusion and exclusion criteria before allergen and continuation criteria on repeat challenges are required to ensure subjects’ safety and data integrity.18Sterk P.J. Fabbri L.M. Quanjer P.H. Cockcroft D.W. O'Byrne P.M. Anderson S.D. et al.Airway responsiveness. Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Report of the Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society.Eur Respir J (Suppl). 1993; 16: 53-83Crossref PubMed Google Scholar Allergen challenge should never be performed in patients with severe asthma, unstable asthma, or both. Recommendations are summarized in Table I (also see Table E1 in this article's Online Repository at www.jacionline.org).Table ISubject inclusion/exclusion criteria for allergen challenge and asthma stability criteria at repeat challengesInclusion criteria Age: 18-55 y; overall good health (especially no cardiovascular problems or chronic sinusitis); good understanding of asthma, precipitating factors, and medication use; willing to comply with the protocol’s rules and capable of performing spirometry well Well-defined, physician-diagnosed, clinically stable asthma; baseline (ie, preallergen) FEV1 ≥70% of predicted value at screening and ≥65% or ≥2 L during subsequent study periods; baseline PC20(methacholine) or histamine <16 mg/mL at screening Able to refrain from controller medications, as defined in Table E1, without clinically relevant asthma worsening throughout the study; stable, infrequent, as-required short-acting rescue medication use only; stable FEV1 and PC20(methacholine or histamine) criteria Demonstrated allergy (skin prick test or blood test) to aeroallergens with a clinical relationship between allergen exposure and asthma symptoms (see the text in this article's Online Repository for the choice of inhaled allergen); if multisensitized and symptomatic, the allergen challenge should be performed outside the relevant allergen exposure or season No relevant bronchoconstriction (ie, ≤10% decrease in FEV1 from baseline) 10 min after inhalation of the allergen’s diluent Current nonsmokers (stopped at ≥6-12 mo ago; ≤10 pack years) No caffeine-containing drinks or products within at least 8 h of bronchoprovocation testing No viral or other respiratory tract infections within ≥4 wk before challengeExclusion criteria Bronchoconstriction at screening (baseline, preallergen FEV1 <70% of predicted or <2 L) or at repeat challenges (study periods; baseline FEV1 <65% of predicted or <2 L) Spirometry-induced bronchoconstriction (ie, <2 baseline FEV1 measurements of 8 attempts within 5%) Recent (<4 wk) viral respiratory tract infections Recent (<1 y) hospital admission for asthma or frequent asthma exacerbations requiring hospital admission or oral corticosteroids Recent major surgery; history of angina pectoris, myocardial infarction, or compromised left ventricular function; any history of cerebrovascular accident, arterial aneurysm, seizures, untreated hypertension, active hyperthyroidism, active or chronic infection, immunologic disorder, cancer, pregnancy or lactation, severe drug allergy, or history of anaphylaxis Inability to comply with procedures related to allergen challengeStability criteria for repeat challenge Baseline FEV1 and PC20(methacholine or histamine) should be measured at the same time of day during the entire study (ie, within a timeframe of 2-3 h) Baseline (ie, preallergen) FEV1 in study period I in a crossover study should remain within 10% of screening (and ≥65% of predicted), and in subsequent study periods all preallergen baseline values should remain within 10% of the preallergen value in study period I No significant bronchoconstriction within 10 min after inhalation of the diluent (≤10% decrease from baseline) PC20(methacholine or histamine) should be performed (preferably 24 h) before allergen; in a crossover study, study period I, preallergen PC20(methacholine or histamine) should remain within 1 doubling concentration of screening and in the subsequent study periods; preallergen PC20(methacholine or histamine) should remain within 1 doubling concentration of the preallergen value of study period I; if not, postpone the allergen challenge by 1-4 wk, depending on the causeSubject suitability to undergo an allergen challenge will depend on individual characteristics, as judged by a qualified and experienced physician. Open table in a new tab Subject suitability to undergo an allergen challenge will depend on individual characteristics, as judged by a qualified and experienced physician. Allergen administration into the lung can be done by using several inhalation protocols, as described below. Although all inhaled challenge methods highlight some aspects of the allergic airway response, the “provocative inhaled dose” methods combine the advantage of studying both the allergen-induced inflammatory sequelae and the subsequent changes in asthma physiology. Selection of a method and concentration for allergen inhalation is governed by 2 important concerns. The first and most important is subject safety. Administration of an overly large dose of allergen has the potential to produce acute severe local or systemic allergic effects. The second concern is to choose a method that is reproducible. Because it is usually applied as a research tool, the reproducibility required is within-subject repeatability; the need for between-subject reproducibility, which is important for diagnostic challenges, such as methacholine and histamine, is less important. Allergen bronchoprovocation tests are conducted through the administration of progressive serial concentrations (or doses) of the chosen aeroallergen at regular intervals until a given decrease in FEV1 (eg, 20%; ie, the EAR) is achieved. Concentrations (or doses) of allergen for inhalation are made available in a geometric progression, most often doubling concentrations.19Cockcroft D.W. Murdock K.Y. Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergen-induced early asthmatic responses, late asthmatic responses, and increased bronchial responsiveness to histamine.J Allergy Clin Immunol. 1987; 79: 734-740Abstract Full Text PDF PubMed Scopus (215) Google Scholar, 20Ravensberg A.J. van Rensen E.L. Grootendorst D.C. de Kluijver J. Diamant Z. Ricciardolo F.L. et al.Validated safety predictions of airway responses to house dust mite in asthma.Clin Exp Allergy. 2007; 37: 100-107Crossref PubMed Scopus (12) Google Scholar, 21Gauvreau G.M. Boulet L.P. Cockcroft D.W. Fitzgerald J.M. Carlsten C. Davis B.E. et al.Effects of IL-13 blockade on allergen-induced airway responses in mild atopic asthma.Am J Respir Crit Care Med. 2011; 183: 1007-1014Crossref PubMed Scopus (106) Google Scholar Some investigators have used half-log22Roquet A. Dahlen B. Kumlin M. Ihre E. Anstren G. Binks S. et al.Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics.Am J Respir Crit Care Med. 1997; 155: 1856-1863Crossref PubMed Google Scholar (approximately 3.2-fold) or 4-fold23Merget R. Jorres R.A. Heinze E. Haufs M.G. Taeger D. Bruning T. Development of a 1-concentration-4-step dosimeter protocol for methacholine testing.Respir Med. 2009; 103: 607-613Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 24Merget R. Sander I. van Kampen V. Raulf-Heimsoth M. Ulmer H.M. Kulzer R. et al.Occupational immediate-type asthma and rhinitis due to rhodium salts.Am J Ind Med. 2010; 53: 42-46PubMed Google Scholar dose step-ups. Even 10-fold dose step-ups have occasionally been used,17Frølund L. Svendsen U.G. Nielsen N.H. Weeke B. Madsen F. Bronchial allergen challenge: comparison between two different methods of provocation.Clin Allergy. 1987; 17: 439-448Crossref PubMed Google Scholar, 25Merget R. Heger M. Globisch A. Rasche K. Gillissen A. Gebler A. et al.Quantitative bronchial challenge tests with wheat flour dust administered by Spinhaler: comparison with aqueous wheat flour extract inhalation.J Allergy Clin Immunol. 1997; 100: 199-207Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar but this is not recommended for safety reasons. The selection of the starting concentration for the initial allergen challenge, which is frequently referred to as a screening challenge, is based on safety. In the past, investigators have used the weakest of the available allergen concentrations producing a discernible (2-3 mm) wheal on skin prick testing as the starting concentration.26Robertson D.G. Kerigan A.T. Hargreave F.E. Chalmers R. Dolovich J. Late asthmatic responses induced by ragweed pollen allergen.J Allergy Clin Immunol. 1974; 54: 244-254Abstract Full Text PDF PubMed Scopus (93) Google Scholar Although this is safe, it creates the potential for a long challenge procedure. Several investigators have documented that the allergen-induced EAR is dependent on the level of the baseline nonspecific AHR (generally assessed with direct stimuli, either histamine or methacholine)20Ravensberg A.J. van Rensen E.L. Grootendorst D.C. de Kluijver J. Diamant Z. Ricciardolo F.L. et al.Validated safety predictions of airway responses to house dust mite in asthma.Clin Exp Allergy. 2007; 37: 100-107Crossref PubMed Scopus (12) Google Scholar and allergen-specific IgE levels, which are generally assessed by using skin prick test end point dilution titration (lowest concentration producing a 2- to 3-mm wheal),27Killian D. Cockcroft D.W. Hargreave F.E. Dolovich J. Factors in allergen-induced asthma: relevance of the intensity of the airways allergic reaction and non-specific bronchial reactivity.Clin Allergy. 1976; 6: 219-225Crossref PubMed Google Scholar, 28Bryant D.H. Burns M.W. Lazarus L. The correlation between skin tests, bronchial provocation tests and the serum level of IgE specific for common allergens in patients with asthma.Clin Allergy. 1975; 5: 145-157Crossref PubMed Google Scholar, 29Cockcroft D.W. Ruffin R.E. Frith P.A. Cartier A. Juniper E.F. Dolovich J. et al.Determinants of allergen-induced asthma: dose of allergen, circulating IgE antibody concentration, and bronchial responsiveness to inhaled histamine.Am Rev Respir Dis. 1979; 120: 1053-1058PubMed Google Scholar, 30Hill D.J. Shelton M.J. Hosking C.S. Predicting the results of allergen bronchial challenge by simple clinical methods.Clin Allergy. 1982; 12: 295-301Crossref PubMed Google Scholar although theoretically, serology (RAST) could be used.29Cockcroft D.W. Ruffin R.E. Frith P.A. Cartier A. Juniper E.F. Dolovich J. et al.Determinants of allergen-induced asthma: dose of allergen, circulating IgE antibody concentration, and bronchial responsiveness to inhaled histamine.Am Rev Respir Dis. 1979; 120: 1053-1058PubMed Google Scholar A formula to predict the allergen concentration required to produce an EAR (ie, allergen concentration causing a decrease in FEV1 of 20% from baseline) has been developed based on skin prick test end point and PC20(histamine/methacholine) values.5Cockcroft D.W. Murdock K.Y. Kirby J. Hargreave F. Prediction of airway responsiveness to allergen from skin sensitivity to allergen and airway responsiveness to histamine.Am Rev Respir Dis. 1987; 135: 264-267PubMed Google Scholar A prediction equation in house dust mite–sensitive asthmatic patients with only PC20(histamine/methacholine) has also been shown to be effective (Table II).20Ravensberg A.J. van Rensen E.L. Grootendorst D.C. de Kluijver J. Diamant Z. Ricciardolo F.L. et al.Validated safety predictions of airway responses to house dust mite in asthma.Clin Exp Allergy. 2007; 37: 100-107Crossref PubMed Scopus (12) Google Scholar These predictions are accurate to within 2 (80% to 81%) or 3 (92% to 94%) doubling concentrations, and hence it is safe to start 3 concentrations at less than the APC20.Table IIFormulae used to predict the allergen-induced early response (ie, allergen concentration causing a decrease in FEV1 of 20% from baseline) from AHR to PC20(histamine or methacholine) with or without skin prick test5Cockcroft D.W. Murdock K.Y. Kirby J. Hargreave F. Prediction of airway responsiveness to allergen from skin sensitivity to allergen and airway responsiveness to histamine.Am Rev Respir Dis. 1987; 135: 264-267PubMed Google Scholar, 17Frølund L. Svendsen U.G. Nielsen N.H. Weeke B. Madsen F. Bronchial allergen challenge: comparison between two different methods of provocation.Clin Allergy. 1987; 17: 439-448Crossref PubMed Google ScholarPredicting allergen-induced EAR (APC20) from AHR (PC20[histamine] or PC20[methacholine]) and titrated SS5Cockcroft D.W. Murdock K.Y. Kirby J. Hargreave F. Prediction of airway responsiveness to allergen from skin sensitivity to allergen and airway responsiveness to histamine.Am Rev Respir Dis. 1987; 135: 264-267PubMed Google Scholar:log10(APC20) = 0.68 × log10(PC20[histamine or methacholine] × SS)Predicting house dust mite∗Equation by Ravensberg et al based on allergen challenges with inhaled house dust mite extract only.20–induced EAR (APC20) from AHR (PC20[methacholine] only)20Ravensberg A.J. van Rensen E.L. Grootendorst D.C. de Kluijver J. Diamant Z. Ricciardolo F.L. et al.Validated safety predictions of airway responses to house dust mite in asthma.Clin Exp Allergy. 2007; 37: 100-107Crossref PubMed Scopus (12) Google Scholar:log10(APC20) = −0.902 + 0.741 × log10(PC20[methacholine])APC20, Allergen PC20 predicted value (predicted provocative allergen dose required to produce a 20% decrease from baseline FEV1); SS, skin prick test end point.∗ Equation by Ravensberg et al based on allergen challenges with inhaled house dust mite extract only.20Ravensberg A.J. van Rensen E.L. Grootendorst D.C. de Kluijver J. Diamant Z. Ricciardolo F.L. et al.Validated safety predictions of airway responses to house dust mite in asthma.Clin Exp Allergy. 2007; 37: 100-107Crossref PubMed Scopus (12) Google Scholar Open table in a new tab APC20, Allergen PC20 predicted value (predicted provocative allergen dose required to produce a 20% decrease from baseline FEV1); SS, skin prick test end point. There are a number of points to make about these prediction equations. First and most important, the prediction equations are method specific. For the derivation of the equations described above, histamine/methacholine and allergen inhalation were conducted by usi
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