Bronchodilator response following methacholine-induced bronchoconstriction predicts acute asthma exacerbations

Heung-Woo Park, Woo-Jung Song, Yoon-Suk Chang, Sang-Heon Cho, Soma Datta, Scott T. Weiss, Kelan G. Tantisira
European Respiratory Journal 2016 48: 104-114; DOI: 10.1183/13993003.00182-2016

Abstract

Methacholine bronchial provocation test provides the concentration of methacholine causing a 20% decrease in forced expiratory volume in 1 s (FEV1) from baseline (PC20). The dose–response slope (DRS), and other continuous indices of responsiveness (CIR; the percentage decline from the post-diluent baseline FEV1 after the last dose of methacholine), and per cent recovery index (PRI; the percentage increase from the maximally reduced FEV1 after bronchodilator inhalation) are alternative measures. The clinical relevance of these indices in predicting acute asthma exacerbations has not been fully evaluated.

In two prospective cohorts of childhood and elderly asthmatics, baseline PC20, DRS, CIR and PRI were measured and evaluated as predictors of acute asthma exacerbations.

We found that PRI was significantly related to the presence of asthma exacerbations during the first year of follow-up in both cohorts of childhood (p=0.025) and elderly asthmatics (p=0.003). In addition, PRI showed a significant association with the total number of steroid bursts during 4.3 years of follow-up in the cohort of childhood asthmatics (p=0.04).

We demonstrated that PRI, an index of reversibility following methacholine-induced bronchoconstriction, was a good clinical predictor of acute exacerbations of asthma in both childhood and elderly asthmatics.

Abstract

Bronchodilator response following methacholine-induced bronchoconstriction may predict acute asthma exacerbations http://ow.ly/ZguI2

Introduction

In clinical practice, the methacholine bronchial provocation test (MBPT) is widely used to measure airway hyperresponsiveness (AHR), which is one of the defining features of asthma [1]. When we interpret the results of MBPT, we usually focus only on the threshold causing a 20% decrease in forced expiratory volume in 1 s (FEV1) from baseline (i.e. PC20 or PD20). However, MBPT provides us other metrics of AHR, such as dose–response slope (DRS; the per cent decline in FEV1 per methacholine dose) [2, 3], the continuous index of responsiveness (CIR; the per cent decline from the post-diluent baseline FEV1 after the last dose of methacholine) [3] and the per cent recovery index (PRI; the per cent increase from the maximally reduced FEV1 after bronchodilator inhalation) [4]. DRS and CIR are indicators of airway responsiveness in the presence of a bronchoconstrictor and reflect the severity of response by assessing the intensity of bronchoconstriction [2, 3]. In stable asthma, the health-related quality of life is not related to the sensitivity index (PC20) but rather to the reactivity index (DRS and CIR) [5]. PRI has been used to assess efficacy of anti-asthmatic drugs [6, 7]. However, the clinical implications of these other metrics of AHR have not been fully evaluated.

Asthmatics sometimes experience an acute deterioration of symptoms, termed an “exacerbation”. Even among asthmatics with controlled asthma, 43% had an unscheduled hospital visit, 10% had an emergency department visit and 3% had a hospitalisation in the past year [8]. The social and economic burden of asthma exacerbations remains considerable [9, 10]. Previously, we reported that pre-bronchodilator FEV1 was negatively correlated with asthma exacerbation in asthmatic children [11]. Other physiological parameters that predict asthma exacerbations include forced expiratory flow between 25 and 75% of vital capacity in the setting of normal FEV1 [12], peripheral airway impulse oscillometry [13] and peak expiratory flow rate [14]. However, there have been no reports comprehensively showing the role of indices obtained from MBPT in predicting asthma exacerbations.

The purpose of this study was to evaluate the clinical utility of measures (PC20, DRS, CIR, and PRI) generated from MBPT in assessing the future risk of asthma exacerbations. For this, we investigated the relationship between baseline values of the MBPT indices and asthma exacerbations in two prospective cohorts composed of childhood and elderly asthmatics.

Methods

Each study was approved by the Institutional Review Board of the corresponding institution (Seoul National University Hospital, Seoul, Korea (number: 0812-045-266) and Brigham and Women's Hospital, Boston, MA, USA (number: 2004-P-000996) and informed consent was obtained from all study participants.

Study populations

The first cohort consisted of children from the Childhood Asthma Management Programme (CAMP) trial. CAMP demographics and study design have been described elsewhere [15, 16]. A total of 1041 children with mild-to-moderate asthma aged 5–12 years were enrolled; a positive MBPT test (PC20 <12.5 mg·mL−1) was an entry criteria for the CAMP trial. At baseline, the number of hospitalisations or emergency room visits in the past 12 months was measured. The children were randomised to budesonide, nedocromil or placebo and followed for a mean of 4.3 years. The total number of prednisone bursts and the total number of hospitalisations or emergency room visit during the study period were calculated. An acute exacerbation was defined if patients experienced one or more prednisone bursts, hospitalisations or emergency room visits.

The second cohort consisted of elderly asthmatics aged ≥65 years that were recruited from Seoul National University Hospital, Seoul and Bundang Seoul National University Hospital, Bundang, Korea. It was a subset of a prospective, observational multicentre cohort in Korea with the purpose of studying the natural history of asthma among elderly people [17]. History of a previous exacerbation (no versus yes) was assessed using a careful review of the medical records from 3 months before enrolment. Cognitive function was assessed using the Korean version of the Mini-Mental State Examination, and mood was assessed using the Korean version of the Geriatric Depression Scale Short Form. Proficiency in using inhaler devices was rated using a scoring system. After baseline evaluations, elderly adults with asthma who were enrolled were treated for 1 year with conventional medications based on the Global Initiative for Asthma guidelines [18]. Follow-up visits were scheduled every 3 months, and the occurrence of asthma exacerbations during the past 3 months was recorded at every visit. An asthma exacerbation was defined when one of the following criteria was satisfied: use of systemic corticosteroids for at least three successive days, asthma-specific unscheduled visits, and emergency department visits or hospitalisations.

Methacholine bronchial provocation test and index analysed

In the CAMP cohort, MBPT was carried out before randomisation using the method of 2 min of tidal breathing from a Wright nebuliser (Bayview Medical Supply, Baltimore, MD, USA) [19]. Children inhaled incrementally doubling doses of methacholine from 0.098 to 12.5 mg·mL−1 until there was a 20% fall from the post-saline FEV1. Then a bronchodilator (two puffs of salbutamol) was administrated and FEV1 was measured 15 min after bronchodilator inhalation. In the elderly cohort, MBPT was carried out using the modified method described by Chai et al. [20]. Concentrations of 1.25, 2.5, 6.25, and 12.5 mg·mL−1 of methacholine were prepared by dilution with buffered saline. A Rosenthal–French dosimeter (Laboratory for Applied Immunology, Baltimore, MD, USA) was used to deliver the aerosol generated by a DeVilbiss 646 nebuliser (Medical Depot, Inc., Port Washington, NY, USA). Subjects inhaled five inspiratory capacity breaths of increasing concentrations of methacholine until FEV1 fell by more than 20% of its baseline value. Then a bronchodilator (two puffs of salbutamol) was administrated and FEV1 was measured 15 min after bronchodilator inhalation.

Figure 1 shows how indices from the MBPT were calculated. PC20 was calculated by interpolation from the last two concentrations. DRS, CIR and PRI were calculated as follows:Embedded ImageEmbedded ImageEmbedded Image

FIGURE 1
FIGURE 1

Indices generated from the methacholine bronchial provocation test. FEV1: forced expiratory volume in 1 s; BD: bronchodilator; MCH: methacholine; PC20: concentration of methacholine causing a 20% decrease in FEV1 from baseline.

All indices were natural log-transformed.

Statistical analysis

A regression analysis (with a logistic regression for the categorical variable and a linear regression for the continuous variable) was performed to evaluate the predictive roles of each index in both cohorts for exacerbations. In the CAMP cohort, age, sex (female versus male), body mass index (BMI) z-score, baseline FEV1 % predicted, history of exacerbation during the previous 1 year (no versus yes), race (Caucasian versus African-American versus Hispanic-American versus Asian-American) and treatment group (placebo versus nedocromil versus inhaled corticosteroid) were included as covariates. The primary outcome was the presence of exacerbations within the first year (categorical variable). Secondary outcomes included per cent increase in FEV1 from the baseline value 8 weeks after treatment, and cumulative number of hospitalisations or emergency room visits at 4 years of follow-up (continuous variables). Covariates in the elderly asthma cohort included age, sex (female versus male), BMI, baseline FEV1 % predicted, smoking status (no versus yes), history of exacerbation during previous 1 year (no versus yes), cognitive function, depression status and inhaler technique. As with CAMP, the primary outcome was the occurrence of exacerbations within 1 year after enrolment (categorical variable). A p-value of <0.05 was considered significant. All analyses were performed with R version 2.15.3 (www.r-project.org). R scripts can be found in the online supplementary material.

Results

Table 1 summarises the baseline characteristics of the childhood and the elderly asthmatics.

View this table:
TABLE 1

Baseline characteristics

Cohort of childhood asthmatics

Pearson's correlation coefficients were measured to assess interdependency of indices generated from MBPT at baseline. High correlations were noted except between ln(PC20) and ln(CIR) (table E1 and figure E1). To evaluate roles of each index in predicting clinical outcomes, regression models were constructed using age, sex, race, BMI z-score, FEV1 predicted value, treatment group, history of past exacerbation and the four indices of responsiveness. Using the variance inflation factor, we evaluated the severity of multicollinearity in our models. The variance inflation factor enables us to measure how much the variance of an estimated regression coefficient is increased because of collinearity [21]. By removing ln(DRS) from our models we could obtain acceptable variance inflation factor values (<5) (table E2). Accordingly, ln(DRS) was excluded from the final model. The results of the regression analysis are presented in table 2. ln(PC20) and ln(PRI) showed significant associations with incident exacerbations at 1 year. The odds ratio obtained from logistic regression analysis was 2.23 (95% CI 1.11–4.54). ln(PRI) also showed a significant association with cumulative numbers of steroid bursts at 4.3 years, but ln(PC20) did not. There were no other associations between MBPT indices and any of the other clinical outcomes.

View this table:
TABLE 2

Relationships between the methacholine bronchial provocation test indices and clinical outcomes in the CAMP childhood asthmatics

Cohort of elderly asthmatics

Unlike childhood asthmatics, high correlations were noted among all pairs of MBPT indices (table E1 and figure E1). After collinearity diagnostics, the final logistic regression model included age, sex, BMI, baseline FEV1 % predicted, smoking status, history of exacerbation during the previous 1 year, cognitive function, depression status, ln(PC20), ln(DRS), ln(CIR) and ln(PRI) (table E3). Among the indices generated from MBPT, only ln(PRI) was significantly associated with incident exacerbations at 1 year (table 3). The odds ratio obtained from logistic regression analysis was 59.88 (95% CI 4.65–1228.76). Figure 2 shows that the ln(PRI) of asthmatics who experienced an acute exacerbations during the first year of follow-up was significantly higher when compared with ln(PRI) of those who did not in both cohorts of childhood and elderly asthmatics. Comparisons of the characteristics between the two groups in both cohorts are presented in table E4 and E5.

View this table:
TABLE 3

Relationship between variables and acute exacerbations in the cohort of elderly asthmatics

FIGURE 2
FIGURE 2

Comparison of the natural logarithm of per cent recovery index (ln(PRI)) between asthmatics who experienced acute exacerbations during the first year of follow-up and asthmatics who did not experience an acute exacerbation. a) Childhood asthmatics. b) Elderly asthmatics. The horizontal lines represent the median and boxes represent the interquartile range (IQR; Q1–Q3). Whiskers represent Q1−1.5×IQR (lower) and Q3+1.5×IQR (upper).

Discussion

MBPT is easy to perform and thus is widely used in clinical practice to diagnose asthma. In the present study, we evaluated the role of four measures (PC20, DRS, CIR and PRI) obtained from MBPT in predicting future risk of asthma exacerbations. We found that PRI, the degree of response to bronchodilator after methacholine-induced bronchoconstriction, was significantly related to the occurrence of asthma exacerbations within 1 year of follow-up in two prospective cohorts of childhood and elderly asthmatics. In addition, PRI showed a significant association with the total number of steroid bursts within 4.3 years of follow-up in the cohort of childhood asthmatics. Of note, while PRI was a predictive marker of exacerbations in both children and elderly adults, the magnitude of effect was higher in the elderly adult cohort (OR 2.2 versus 59.9 for children versus adults, respectively), suggesting particular prognostic and therapeutic relevance in that cohort. Recently, it was reported that DRS showed clinical advantages over PC20 for the prediction of development of asthma, chronic obstructive pulmonary disease and allergic rhinitis in the general population [22]. Clinically, it seems that DRS may be more important in subjects without definite AHR defined by PC20. However, in asthmatics, DRS was tightly correlated with PC20 as our results showed and thus may have no more clinical relevence than PC20. To the best of our knowledge, this is the first study to show a promising role for bronchodilator response following methacholine-induced bronchoconstriction in predicting asthma exacerbations.

Early reports showed that the degree of airway sensitivity and responsiveness to methacholine (PC20, DRS and CIR in this study) could be markers of asthma severity [23–25]. It is natural to expect that asthmatics with increased airway sensitivity and responsiveness are more susceptible to bronchoconstriction when they are exposed to nonspecific stimuli. However, it was reported that inhaled corticosteroid treatment gradually decreased airway hypersensitivity and hyperresponsiveness [26, 27]. These findings suggested that airway sensitivity and responsiveness index measured at baseline could not predict future asthma exacerbations as long as proper medications were provided. Hancox et al. [4] first introduced the challenge-rescue technique to assess bronchodilator response. Similar to the present study, they measured bronchodilator response after airway smooth muscle contraction induced by methacholine. PRI reflects the efficacy of bronchodilator medications in the environment causing maximal contraction of airway smooth muscle, as shown in the previous study [6, 7]. Airway smooth muscle of asthma patients was found to be abnormal in its functional properties and showed intrinsic heightened contractility independent of other structural cells and independent of the airway inflammatory milieu [28, 29]. At present, we cannot measure how much airway smooth muscle contraction contributes to AHR. Recent studies, which showed that anti-IgE or anti-interleukin-5 antibodies in addition to inhaled corticosteroids further improved inflammation but did not affect AHR, implied that a bronchodilator might have its own role in the management of asthma [30–32]. In addition, we observed that PRI was not associated with airway eosinophilic inflammation of elderly asthmatics (figure E2). Taken together, we may assume that sufficient bronchodilator treatment is important for the effective management of asthmatics with high PRI. In CAMP, ∼5% of asthmatic children randomised to the inhaled corticosteroid arm showed consistent bronchodilator responses over the 4-year trial and they had more hospital visits and required more prednisone bursts [33]. It is possible that maintenance treatments of bronchodilator were essential in certain cases. Namely, asthmatic children with a high PRI should have been managed with maintenance treatments of bronchodilator, including a combination therapy with inhaled corticosteroid and long-acting β2-agonist, to reduce acute exacerbations. Another possible explanation is that asthmatic children with a high PRI might feel better symptomatic improvement compared with those with a low PRI when they used a short-acting β2-agonist as a reliever medication. Actually, we found a positive correlation with a borderline significance (p=0.043) between ln(PRI) and the use of salbutamol (a short-acting β2-agonist) during the first 8 weeks of follow-up in the CAMP childhood asthmatics (figure E3). As noted previously, an effective bronchodilation through a short-acting β2-agonist therapy might mask symptoms of deteriorating asthma and lead to asthma exacerbations [34].

The elderly asthma cohort were treated with a combination of inhaled corticosteroid and bronchodilator (a long-acting β2-agonist) as recommended by the current guidelines [18]. Despite a long-acting β2-agonist therapy, a subset of this cohort continued to have an elevated PRI with very high likelihood of subsequent exacerbations (OR 59.88 (95% CI, 4.65–1228.76)). We postulate that a maintenance treatment of long-acting β2-agonist was not sufficient for elderly asthmatics with a high PRI. AHR was persistently observed even in the absence of airway inflammation following long-term use of ICS [35], which suggested that other pathophysiological factors, such as increased cholinergic and smooth muscle tone, might have a role in asthma [36, 37]. In accordance, tiotropium, a long-acting anti-cholinergic, as add-on to inhaled corticosteroid plus long-acting β2-agonist, was found to be associated with a reduction in the number of asthma exacerbations [38, 39]. Therefore, it was possible that intensive bronchodilator treatments including long-acting β2-agonists and long-acting anti-cholinergic agents would be needed for elderly asthmatics with high PRI.

The present study has notable strengths and weaknesses. The clinical relevancy of PRI was demonstrated in two populations at the extremes of age, that is, childhood and elderly asthmatics. As pulmonary function testing is known to be affected by age [40, 41], there may be concerns as to the accuracy of pulmonary function measurement in these extreme groups. However, preschool children and the elderly were capable of performing spirometry under the supervision of well-trained technicians [41–43]. Thus, the data in the present study are of high quality. A prospective study design of two cohorts is one of the strengths of the present study. However, we did not confirm that PRI is an invariant characteristic after long-term asthma treatments. If PRI improved after long-term asthma treatments, the clinical relevance of PRI measured at baseline in predicting asthma exacerbations would decrease as shown by a rise in the baseline PC20. In addition, an ethnicity difference needs to be considered in generalising our observations. Most subjects in the childhood cohort were Caucasian or African-American, but the elderly cohort was entirely Asian. A difference in ethnicity introduces both possible environmental and genetic variation and potentially alters the therapeutic efficacy of bronchodilators [44]. Finally, statistical issues need to be considered. The data used in the present study were gathered for another purpose and thus multiple testing was prone to type I errors. Bonferroni correction (multiplied by four (four comparable dependent variables)) effaced the significance of ln(PRI). In addition, it has been reported that logistic regression analysis in studies with a small sample size overestimated odds ratios [45]. The high odds ratio in elderly asthmatics should be reassessed in another cohort.

In conclusion, we demonstrated that PRI, an index of bronchodilator response following methacholine-induced bronchoconstriction, was a good clinical factor for predicting acute asthma exacerbations in both childhood and elderly asthmatics. An intensive bronchodilator treatment including a long-acting anti-cholinergic agent may be necessary for asthmatics with a high PRI.

Acknowledgements

CAMP credit roster

Source of funding: the CAMP trial and CAMP continuation study were supported by contracts NO1-HR-16044, 16045, 16046, 16047, 16048, 16049, 16050, 16051, and 16052 with the National Heart, Lung, and Blood Institute and General Clinical Research Center grants M01RR00051, M01RR0099718-24, M01RR02719-14, and RR00036 from the National Center for Research Resources. The CAMP continuation study/phases 2 and 3 were supported by grants U01HL075232, U01HL075407, U01HL075408, U01HL075409, U01HL075415, U01HL075416, U01HL075417, U01HL 075419, U01HL075420, and U01HL075408 from the National Heart, Lung, and Blood Institute.

Members of the CAMP Research Group

Clinical centers

ASTHMA, Inc., Seattle, WA, USA: Paul Williams (Principal investigator); Mary V. Lasley (Co-director); Tamara Chinn (Coordinator); Michele Hinatsu; Clifton T. Furukawa; Leonard C. Altman; Frank S. Virant; Michael S. Kennedy; Jonathan W. Becker; Stephen Tilles; Miranda MacLaren. C. Warren Bierman (1992–1997); Dan Crawford (1996–2002); Thomas DuHamel (1991–2004); Heather Eliassen (1996–1999); Babi Hammond (1996–1999); Dominick A. Minotti (1992–2003); Chris Reagan (1992–2003); Gail Shapiro (1991–2006, Principal investigator); Marian Sharpe (1992–1994); Ashley Tatum (2004–2007); Grace White (1991–2007); Timothy G. Wighton (1994–1998).

Brigham and Women's Hospital, Boston, MA, USA: Anne Fuhlbrigge (Principal investigator); Anne Plunkett (Coordinator). Nancy Madden; Mark Boehnert; Christine Darcy; Anita Feins; Natalia Kandror; Kelly MacAulay; Scott Weiss; Walter Torda (Co-investigator director, 1993–2003); Martha Tata (1993–2002); Sally Babigian (1997–1999); Peter Barrant (2004–2007); Linda Benson (1998–2004); Jose Caicedo (1998–1999); Tatum Calder (1998–2001); Anthony DeFilippo (1994–2000); Cindy Dorsainvil (1998–2001); Julie Erickson (1998–1999); Phoebe Fulton (1997); Mary Grace (1994–1996); Jennifer Gilbert (1997–1998); Dirk Greineder (1993–2000); Stephanie Haynes (1993–1998); Margaret Higham (1996–1998); Deborah Jakubowski (1999); Susan Kelleher (1993–1997); Jay Koslof (1993–1995); Dana Mandel (1996–1998); Patricia Martin (2001–2003); Agnes Martinez (1994–1997); Jean McAuliffe (1994–1995); Erika Nakamoto (2002–2004); Paola Pacella (1993–1998); Paula Parks (1993–1995); Johanna Sagarin (1998–1999); Kay Seligsohn (1995–2004); Susan Swords (2003–2005); Meghan Syring (1998–2001); June Traylor (1996–1998); Melissa Van Horn (1996–1999); Carolyn Wells (1993–1995); Ann Whitman (1994–1996).

The Hospital for Sick Children, Toronto, ON, Canada: Hartmut Grasemann (Principal investigator); Melody Miki (Coordinator); Melinda Solomon; Padmaja Subbarao. Ian MacLusky (Director 1999–2007); Joe Reisman (Director, 1996–1999); Henry Levison (Director, 1992–1996); Anita Hall (Coordinator, 1993–2007). Yola Benedet (1994–1999); Susan Carpenter (1998–2001); Jennifer Chay (2004); Michelle Collinson (1994–1998); Jane Finlayson-Kulchin (1994–1998); Kenneth Gore (1993–1999); Nina Hipolito (2003–2004); Noreen Holmes (1998–1999); Erica Hoorntje (2002–2003); Sharon Klassen (1999–2000); Josee Quenneville (1993–1995); Renee Sananes (1993–2004); Christine Wasson (1999); Margaret Wilson (2001–2002).

Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA: N. Franklin Adkinson, Jr (Director); Deborah Bull (Coordinator); Stephanie Philips. Peyton Eggleston (Co-director, 1991–2004); Karen Huss (Co-investigator, 1991–2004); Leslie Plotnick (Co-investigator, 1991–1999); Margaret Pulsifer (Co-investigator, 1993–2004); Cynthia Rand (Co-Investigator, 1991–2004). Elizabeth Aylward (1991–2004), Nancy Bollers (Coordinator, 1993–2004); Kathy Pessaro (2004–2007); Barbara Wheeler (Coordinator, 1991–1999).

National Jewish Health, Denver, CO, USA: Stanley Szefler (Director); Harold S. Nelson (Co-director); Bruce Bender (Co-investigator); Ronina Covar (Co-investigator); Andrew Liu (Co-investigator); Joseph Spahn (Co-investigator); D. Sundstrom (Coordinator); Melanie Phillips; Michael P. White; Melanie Gleason; Marzena Krawiec; Gary Larsen; Gayle Spears. Kristin Brelsford (1997–1999); Jessyca Bridges (1995–1997); Jody Ciacco (1993–1996); Michael Eltz (1994–1995); Jeryl Feeley (Coordinator, 1992–1995); Michael Flynn (1995–1996); Tara Junk-Blanchard (1997–2000); Joseph Hassell (1992–1998); Marcia Hefner (1992–1994); Caroline Hendrickson (1995–1998; Coordinator, 1995–1997); Daniel Hettleman (1995–1996); Charles G. Irvin (1992–1998); Alan Kamada (1994–1997); Sai Nimmagadda (1993–1996); Kendra Sandoval (1995–1997); Jessica Sheridan (1994–1995); Trella Washington (1993–1997); Eric Willcutt (1996–1997). We also thank the paediatric allergy/immunology and pulmonary fellows for their participation (Ivan Cardona; Kirstin Carel; Jayna Doshi; Rich Hendershot; Jeffrey Jacobs; Neal Jain; June-ku Brian Kang; Tracy Kruzick; Harvey Leo; Beth Macomber; Jonathan Malka; Chris Mjaanes; John Prpich; Lora Stewart; Ben Song; Grace Tamesis).

University of California, San Diego, and Kaiser Permanente Southern California Region, San Diego, CA, USA: Robert S. Zeiger (Director); Noah Friedman (Co-investigator); Michael H. Mellon (Co-investigator); Michael Schatz (Co-investigator); Kathleen Harden (Coordinator). Terrie Long; Travis Macaraeg; Elsa Rodriguez; Eva Rodriguez. Sandra Christensen (2004–2007); James G. Easton (Co-director, 1993–1994); M. Feinberg (1997–1998); Linda L. Galbreath (1991–2002); Jennifer Gulczynski (1998–1999); Ellen Hansen (1995–1997); Al Jalowayski (Co-investigator, 1991–2005); Elaine Jenson (2004–2007); Alan Lincoln (Co-investigator, 1991–2003); Jennie Kaufman (1994); Shirley King (1992–1999); Brian Lopez (1997–1998); Michaela Magiari-Ene (1994–1998); Kathleen Mostafa (1994–1995); Avraham Moscona (1994–1996); Catherine A. Nelle (1991–2005); Jennifer Powers (2001–2003); Karen Sandoval (1995–1996); Nevin W. Wilson (Co-director, 1991–1993).

University of New Mexico, Albuquerque, NM, USA: H. William Kelly (Director); Aaron Jacobs (Co-investigator); Hengameh H. Raissy (Co-investigator); Mary Spicher (Coordinator); Christina Batson; Robert Annett (Co-investigator, 1993–2004); Teresa Archibeque (1994–1999); Naim Bashir (Co-investigator, 1998–2005); H. Selda Bereket (1995–1998); Marisa Braun (1996–1999); Carrie Bush (1995–1999); Shannon C. Bush (2002–2007); Michael Clayton (Co-investigator, 1999–2001); Angel Colon-Semidey (Co-investigator, 1997–2000); Sara Devault (1993–1997); Anna Esparham (2004–2007); Roni Grad (Co-investigator, 1993–1995); David Hunt (1995–2004); Jeanne Larsson (1995–1996); Katie McCallum (2009); Sandra McClelland (Coordinator, 1993–1995); Bennie McWilliams (Co-investigator, Director, 1992–1998); Elisha Montoya (1997–2000); Margaret Moreshead (1996–1999); Shirley Murphy (Co-investigator, 1992–1994); Barbara Ortega (1993–1999); David Weers (1997–1998); Jose Zayas (1995–1996).

Washington University, St Louis, MO, USA: Robert C. Strunk (Director); Leonard Bacharier (Co-investigator); Gordon R. Bloomberg (Co-investigator); Denise Rodgers (Coordinator); Ellen Albers (1999–2003); James M. Corry (Co-investigator, 1995–2004); Karen DeMuth (2006–2007); Lila Kertz (2005–2007); Valerie Morgan (2004–2007); Cynthia Moseid (2007); Tina Oliver-Welker (1993–2007); Deborah K. White (1993–2007).

Resource centers

Data Coordinating Center, The Johns Hopkins University, Baltimore, MD, USA: James Tonascia (Director); Patricia Belt; Karen Collins; Betty Collison; Ryan Colvin; John Dodge; Michele Donithan; Cathleen Ewing; Rosetta Jackson; Hope Livingston; Jill Meinert; Girlie Reyes; Michael Smith; Alice L. Sternberg; Mark L. Van Natta; AnnetteWagoner; Laura Wilson; Robert Wise; Katherine Yates.

Project Office, National Heart, Lung, and Blood Institute, Bethesda, MD, USA: Virginia Taggart (Project officer); Lois Eggers; James Kiley; Howard Moore; Gang Zheng. Paul Albert (1991–1999); Suzanne Hurd (1991–1999); Sydney Parker (1991–1994); Pamela Randall (1992–2003); Margaret Wu (1991–001).

Committees

Data and Safety Monitoring Board: Michelle Cloutier (Chair); John Connett; Leona Cuttler; Frank Gilliland. Clarence E. Davis (1993–2003); Howard Eigen (1993–2009, Chair); David Evans (1993–2007); Meyer Kattan (1993–2007); Rogelio Menendez (1993–2007); F. Estelle R. Simons (1993–2007); Sanford Leikin (1993–1999).

Steering Committee: Robert Strunk (Study chair); N. Franklin Adkinson; Robert Annett (1992–1995, 1997–1999); Bruce Bender; Mary Caesar (1994–1996); Reuben Cherniack (Study chair 1993–2007); Thomas R. DuHamel (1992–1994, 1996–1999); Anne Fuhlbrigge; Hartmut Grasemann; H. William Kelly; Henry Levison (1992–1996); Alan Lincoln (1994–1995); Ian MacLusky (1999–2006); Bennie McWilliams (1992–1998); Curtis L. Meinert; Sydney Parker (1991–1994); Joe Reisman (1991–1999); Denise Rodgers; Kay Seligsohn (1996–1997); Gail G. Shapiro (1991–2006); Marian Sharpe (1993–1994); D Sundstrom (1998–1999); Stanley Szefler; Virginia Taggart; Martha Tata (1996–1998); James Tonascia; Scott Weiss; Barbara Wheeler (1993–1994); Paul Williams; Robert Wise; Robert Zeiger.

Footnotes

  • This article has supplementary material available from erj.ersjournals.com

  • Support statement: This work was supported by the National Institute of Health, US (R01 NR013391 and U01 HL065899) and by the Ministry of Health and Welfare, Republic of Korea (2008-E33028-00, 2009-E33022-00 and 2011-E33005-00). Funding information for this article has been deposited with FundRef.

  • Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com

  • Received November 6, 2015.
  • Accepted March 1, 2016.

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Bronchodilator response following methacholine-induced bronchoconstriction predicts acute asthma exacerbations
Heung-Woo Park, Woo-Jung Song, Yoon-Suk Chang, Sang-Heon Cho, Soma Datta, Scott T. Weiss, Kelan G. Tantisira
European Respiratory Journal Jul 2016, 48 (1) 104-114; DOI: 10.1183/13993003.00182-2016
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