Conditions: Lung Diseases Medication Compliance
Keywords: World Trade Center Disaster Environmental Exposure Respiratory Physiology Inflammation Gastrointestinal Diseases Sinus Symptoms PTSD Anxiety Depression Hypersensitivity Spirometry Oscillometry
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
The purpose of this study is to understand why patients in the World Trade Center program have continuing breathing problems. This study will improve investigators understanding of breathing problems among individuals with World Trade Center exposure by allowing them to review and monitor medication use, lung function, and examine other conditions that can contribute to problems with breathing. The findings from the study will help investigators understand why some people have persistent lower respiratory symptoms (breathing problems) after their exposure to World Trade Center dust and fumes, and may help guide better management and treatment of these symptoms.

Detailed description:
Investigators will conduct a clinical study with aggressive treatment for lower respiratory symptoms in patients in the World Trade Center Environmental Health Center. Patients in the WTC EHC with uncontrolled LRS at visit 1 will be identified and placed on high-dose inhaled corticosteroids and long-acting beta agonists for three months. Adherence will be assessed at monthly visits. Patients will perform spirometry and oscillometry at baseline and after 3 months of treatment. They will also be assessed for markers of airway inflammation, bronchial hyperresponsiveness and co-morbid conditions including depression,anxiety,post-traumatic stress disorder, gastroesophageal reflux, paradoxical vocal cord motion and rhinosinusitis.

Arms:
arm 1: Patients who have uncontrolled lower respiratory symptoms (ACT \< 20) at time of Visit 1 will be provided with study Advair (Fluticasone propionate 230mcg/salmeterol 21mcg) for a total of 3 months and receive medication adherence counseling Patients who have uncontrolled LRS at V1, but do not fit criteria for Step 3,4 or 5 asthma therapy according to NIH EPR III asthma guidelines will be deferred from the study until they have been seen by their physician and tried on ICS therapy. arm 2: Patients who had symptoms at monitoring visit but are now controlled at V1 will be asked to continue their current treatment (or no treatment) and will continue with the study. They will not be provided with any medications.

Interventions: intervention 1: Fluticasone propionate 230mcg for 3 Months intervention 2: Current Treatment or no treatment intervention 3: Salmeterol 21mcg for 3 Months
Intervention descriptions: intervention 1: None intervention 2: Patients who had symptoms at monitoring visit but are now controlled at V1 will be asked to continue their current treatment (or no treatment) and will continue with the study. They will not be provided with any medications. intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
S13:00448 Protocol, Version 12. 31.2014 
1 
 
S13-00448: Uncontrolled Lower Respiratory Symptoms in the WTC Survivor Program  
NCT02024204 
Principal Investigator:  Joan Reibman, MD 
 
Co-Investigators: 
Angeliki Kazeros, MD 
 
 
 
Caralee Caplan-Shaw, MD 
 
 
 
Kenneth Berger, MD 
 
 
 
Milan Amin, MD 
 
 
 
Nomi Levy-Carrick, MD 
Bertram Bleck, PhD 
Mengling Liu, PhD 
 
 
 
Karen Carapetyan, MA 
Samantha Kalish, BA 
John Egan, MD 
Catherine Wilkinson,BA 
 
 
 
 
 
 
 
Purpose of the Study 
Exposure to the dust and fumes of the World Trade Center (WTC) disaster resulted in adverse health 
including upper and lower respiratory symptoms in responders and community members. The WTC 
Environmental Health Center (WTC EHC), initiated in 2005, was the first and remains the only treatment 
program that targets community members, now called “Survivors,” including local residents, local workers 
and clean-up workers with WTC dust and fume exposures {  }.  Lower respiratory symptoms (LRS) that 
include cough, wheeze, dyspnea, and chest tightness are prevalent in patients in the WTC EHC. Most 
patients with these symptoms in the “Responder” and “Survivor” programs are diagnosed with asthma and 
this diagnosis has guided therapy. Although spirometry is often normal, diagnosis has been supported by 
studies showing bronchial hyperresponsiveness (BHR) in some {  }{  }, and distal or small airways disease 
measured with impulse oscillometry (IOS) { } { }. As a result, the WTC EHC program has used a treatment 
algorithm based on guidelines for asthma from the National Institutes of Health 1. These guidelines focus 
on the use of “controller” therapy, which includes inhaled corticosteroids (ICS) and long acting 
bronchodilators (LABA) for persistent symptoms. Despite this approach, eleven years after the 
destruction of the WTC towers, many patients in the WTC EHC report incomplete clinical response 
with continued lower respiratory symptoms. In fact, patients with continued uncontrolled lower 
respiratory symptoms (LRS) remain on treatment with long-term high dose ICS often with additional LABA 
use, rendering them at risk for adverse health effects of long term ICS treatment. The persistence of 
symptoms, despite therapeutic interventions, necessitates a reevaluation and a search for causes of 
persistent symptoms. Possibilities include incomplete adherence with medical regimens, continuing 
airways disease (BHR or small airways disease) with persistent lung inflammation, or the presence of co-
morbid conditions. Our overall hypothesis is that WTC EHC patients with uncontrolled LRS despite 
aggressive medical therapy have increased rates of abnormal airway physiology, airway 
inflammation and co-morbid conditions. Identifying mechanisms for uncontrolled LRS is 
imperative to guide therapy with the important potential to reduce secondary adverse health 
outcomes. We will test this hypothesis using a prospective study with the following aims: 
 
Specific Aim 1. To conduct a clinical study with aggressive treatment for lower respiratory 
symptoms in the WTC EHC in order to identify a group of patients with controlled lower respiratory 
symptoms (CLRS) and a group of patients with persistent uncontrolled lower respiratory symptoms 
(ULRS).  


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SA1.a To test whether a three month treatment with combined high dose inhaled corticosteroids (ICS) 
and long acting bronchodilators (LABA) results in improved lower respiratory symptoms in patients 
overall. 
Specific Aim 2. To test the hypothesis that discrete measures of lung physiology are associated with 
the status of ULRS and CLRS in patients in the WTC EHC.  
SA2.a To test whether bronchial hyperresponsiveness (BHR) is associated with the status of ULRS and 
CLRS by comparing rates of BHR in patients with ULRS and CLRS.   
SA2.b To test whether measurements of airflow and lung volume (FEV1, FVC, FEV1/FVC, RV/TLC) and 
of small airway dysfunction (impulse oscillometry) are associated with ULRS and CLRS status.  
Specific Aim 3. To test the hypothesis that inflammatory markers associated with airway disease 
are increased in patients with ULRS compared to CLRS in the WTC EHC.  
SA3.a Compare levels of an exhaled marker of inflammation (Fractional exhaled nitric oxide; FeNO) in 
patients with ULRS and CLRS. 
SA3.b Compare levels of circulating biomarkers associated with a Th2 inflammatory response (total 
and allergen-specific IgE, circulating eosinophils, C-reactive protein, serum periostin) in patients with 
ULRS and CLRS.  
Specific Aim 4. To test the hypothesis that increased rates of co-morbid conditions are associated 
ULRS compared to CLRS in the WTC EHC. 
SA4.a Compare quantitative measures of PTSD, anxiety or depression in patients with ULRS and CLRS. 
SA4.b Compare rates of chronic rhinosinusitis symptoms and probable paradoxical vocal cord motion 
(PVCM) in patients with ULRS and CLRS.  
SA4.c Compare rates of gastroesophageal reflux symptoms in patients with ULRS and CLRS. 
Background 
Exposure to WTC dust/fumes/gas in the “Survivor” population 
The attacks on the WTC on 9/11/01 generated a toxic plume of dust, fumes, and vapors that exposed nearly 
250,000 people on the day of the event, and thousands more during participation in cleanup and 
resumption of work and residence in the area during the aftermath. Those potentially exposed include the 
members of the fire department of New York (FDNY) and the non-FDNY rescue and recovery workers. 
Importantly, over 300,000 community members including those in the daily work force (local workers), 
students, and local residents (residents) 2, 3. Many of these community members were exposed to the acute 
events of 9/11 and were caught in the massive dust clouds created as the WTC buildings collapsed (dust 
cloud). Others returned to work (local workers) or homes (residents) in the following week, or participated 
in the clean up of the surrounding buildings (clean-up workers). These individuals were exposed for 
months to the more chronic fumes and gasses from the fires that burned through December 2001 and the 
resuspended dust from recovery activities, uncleaned streets and buildings, or cleaning efforts. Thus 
community members, or “Survivors” had significant potential for both acute and chronic exposures 
to WTC dust gasses and fumes.  
Indoor and outdoor bulk samples of WTC dust collected after the disaster had an extremely alkaline pH 
and were composed primarily of pulverized building and construction materials, with some contamination 
with lead, asbestos, glass fibers, and polycyclic aromatic hydrocarbons 4. Approximately 90% of the 
particles were > 10 microns in diameter 5. Although the inhalable small particulate fraction of the dust (< 
2.5 microns, PM2.5) was only small percentage of the mass (10%), the quantity of particulate matter 
released was so massive that PM2.5 levels in the surrounding air were extremely high 6. The massive 
quantity of large particles had potential to overcome normal respiratory protective mechanisms and 
indeed, analysis of bronchoalveolar lavage provided evidence that these large fibers lodged in human lungs 


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and caused eosinophilic inflammation 7. Additional studies of induced sputum and biopsies years after the 
event showed continued presence of particles and continued inflammatory cells 8, 9. The particles from 
the WTC dust have potential to cause acute and persistent airway inflammation and can reach large 
and small airways.  
WTC-related lower respiratory symptoms (LRS) in local community members. 
Respiratory symptoms consisting of persistent and often unremitting cough, shortness of breath and 
wheeze were described soon after the WTC destruction initially in firefighters (FDNY) who had a existing 
medical program enabling pre and post-event comparisons 10, 11 , 12-15. Similar findings were described in 
non-FDNY rescue workers 16. Spirometry measurements remained within normal limits in the FDNY, albeit 
with a rapid decline in lung function 11, 13. Persistent bronchial hyperreactivity (BHR) was also noted for a 
small number 13. Information for community members has been more difficult to obtain because of the 
absence of organized advocacy groups (unions etc.). In the first detailed study of local residents, we 
described persistent new-onset lower respiratory symptoms (LRS; cough, dyspnea, wheeze, chest 
tightness) in previously asymptomatic residents 17-20. In this door-to-door field study completed within 2 
years following 9/11, screening spirometry was normal for the group, with nearly, 50% showing BHR in a 
sampled subgroup. These findings of lung symptoms were supported by subsequent studies from the New 
York City (NYC) Department of Health and Mental Hygiene (DOHMH) World Trade Center Registry 
(WTCHR) 2, 3, 21, 22. In collaboration with the WTCHR, we later showed that both chronic and acute 
exposures to the events of 9/11 were independently associated with LRS among local workers and 
residents 23. Moreover, we showed that WTC exposures and LRS were associated with reduced, although 
normal, spirometry measurements and abnormal impulse oscillometry (IOS) suggestive of distal airway 
involvement 24. A separate analysis of BHR in a sampled population in the WTC EHC performed over 6 
years after 9/11 similarly showed a 50% rate of BHR in symptomatic patients with LRS 25. These studies 
support the presence of WTC-related LRS in the community, and suggest the presence of BHR and 
distal airway involvement.  
Treatment program in the WTC Environmental Health Center.  
The World Trade Center Environmental Health Center (WTC EHC) is a treatment program that evolved out 
of our initial studies and was developed in collaboration with community members to target local 
residents, local workers and clean-up workers 26. Initially started as an unfunded community partnership, 
a more formal program was initiated in 2005 with funding from the American Red Cross; funding from the 
City of New York became available in 2006, and in 2008, federal funding was provided. To date, patients 
enter the program only if they have a possible WTC-related symptom. This is not a screening program for 
the asymptomatic person. Patients undergo a standardized initial evaluation with an administered 
questionnaire, physical examination by a physician who often specializes in pulmonary medicine, pre and 
post bronchodilator spirometry and IOS measurements, routine blood tests and a chest X-ray (CXR). In 
addition, patients are screened for symptoms consistent with posttraumatic stress disorder (PTSD), 
depression and anxiety. Of the > 6,000 enrollees to date, most present with persistent LRS with 
nasal/sinus symptoms and symptoms consistent with gastroesophageal reflux (GER). Despite 
initially seeking care for physical symptoms, rates of positive scores for PTSD, anxiety, or depression are 
high, exceeding those described in other exposed populations 27. The need for services in the WTC EHC 
rapidly overwhelmed capacity, necessitating treatment of patients based on clinical symptoms and 
information from other exposed populations. Our treatment approaches are in accordance with national 
and international guidelines and are as follows:   
Respiratory management. Patients with an abnormal CXR, sarcoidosis, or other interstitial lung disease 
undergo individualized studies and treatment including high resolution computerized tomography (HRCT) 
and diagnostic procedures (biopsy etc.). Patients with LRS and an obstructive pattern of spirometry with 
bronchodilator reversibility (an uncommon finding) are treated for asthma 1. Patients with reduced vital 
capacity on spirometry undergo further lung function testing and HRCT. Some patients have undergone 
biopsy 9. Many patients with LRS, normal spirometry and a normal CXR have IOS measurements, which are 


S13:00448 Protocol, Version 12. 31.2014 
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often consistent with small or distal airway dysfunction 28. The diagnosis of asthma is a clinical diagnosis 
based on a constellation of clinical findings and lung function measurements 1, 29, and thus we have treated 
patients with LRS and a normal CXR with normal, obstructive, or a reduced VC as if they had asthma 
according to asthma treatment guidelines 1. Treatment of persistent symptoms is initiated with an anti-
inflammatory controller agent, predominantly ICS with long acting bronchodilators (LABA) added as a 
step-up medication for uncontrolled symptoms 1. Since only a limited number of patients have 
undergone methacholine challenge, we define these patients in this proposal as having LRS rather 
than providing a diagnosis of “asthma.”  
Management of co-morbid symptoms. Co-morbid conditions (gastroesophageal reflux; GER, chronic 
rhinosinusitis, PTSD/depression/anxiety) are also attended to with a treatment algorithm. GER symptoms 
are treated with a proton pump inhibitor, and if persistent, patients are referred to a gastroenterologist. 
Chronic rhinosinusitis is treated with nasal steroids, saline washes and if persistent, these individuals 
undergo sinus CT scans and are referred to a specialist. Patients who score positive for 
PTSD/depression/anxiety are referred to our mental health program, where they undergo further 
diagnostic evaluation and are provided with appropriate therapy. 
Continued LRS in the WTC EHC  
To understand the course of illness in the WTC, we recently examined longitudinal lung function and 
symptoms. Examination of longitudinal spirometry measurements in the WTC EHC suggests that many 
spirometric parameters improved over time 30. However, our review of the presence of persistent LRS 
(present > 2 x/week in the preceding month) in the first patients who returned for a standardized 
monitoring examination (n = 1300), shows that LRS symptoms continue: 56% had persistent cough, 32% 
had wheeze and 50% had any LRS other than cough (Table 1;unpublished data). Thus, the WTC EHC now 
includes a cohort of patients with persistent LRS symptoms, many of whom remain on substantial doses of 
ICS. The continued use of high dose ICS puts these patients at risk for corticosteroid associated 
complications 31. The continued nature of the LRS despite treatment with high dose medications 
necessitates a re-evaluation of the disease process in this population.  
Lung physiology in WTC-exposed patients without other lung disease 
Most studies of WTC-exposed populations report normal spirometry, with some symptomatic patients 
showing a restrictive spirometry pattern (reduced VC), and few showing classic airway obstruction or 
interstitial disease 12, 13, 16, 17. Our initial study of local residents, completed within 2 years post-9/11 
showed BHR in nearly 50% of a sampled group 17. More recently, nearly 50% of a subset of patients with 
normal spirometry in the WTC EHC (n = 100) had BHR using stringent criteria 25 and nearly 70% had BHR 
using IOS as criteria 32. Many patients in the WTC EHC, including those with a reduced VC, also have 
elevated IOS measurements, suggesting the presence of distal or small airway involvement 24, 28, 33. Air 
trapping, consistent with distal airway disease, has also been shown in HRCT studies of responders 34. In 
the absence of abnormal parenchymal lung disease on imaging, these studies support a diagnosis 
of airways disease consistent with “asthma,” but suggest that additional disease mechanisms, 
including the involvement of small airways, need to be considered. 
Inflammation and WTC-related LRS in WTC-exposed patients 
Asthma is a heterogeneous disease with multiple clinical and biologic phenotypes 3536, 37. Differences in 
inflammatory pathways may influence the severity of asthma and the response to treatment 38. Some of 
these inflammatory pathways are refractory to corticosteroids, and thus using ICS in these patients may 
expose them to unnecessary risk. The importance of classifying these phenotypes has recently been 
reinforced in pharmaceutical studies of the anti IL-13 monoclonal antibody, in which high levels of 
periostin, a down-stream IL-13 target, predict response 39. There are few descriptions of lung inflammation 
in patients with WTC-related LRS 40. We recently described peripheral eosinophilia in some, but not all, 
symptomatic WTC EHC patients 41. For our proposed studies, we will follow the current recommendations 
of the NIH for measurements of biomarkers 42 and focus on complete blood counts for circulating 


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eosinophils, fractional exhaled nitric oxide (FeNO), total and allergen-specific IgE and include novel 
measurements of serum periostin 39, 43. Through these studies, we will characterize the inflammatory 
pattern in WTC-related lung disease to help target therapy. 
Co-morbid conditions and LRS in WTC-exposed patients 
It is well accepted that LRS may be caused and complicated by co-morbid conditions 44. We will focus on 
conditions that have been described in the WTC or irritant-exposed populations with potential to modify 
asthma:  
• Upper airway disease and Paradoxical vocal cord motion (PVCM). Nasal, sinus and bronchial diseases 
often coexist and upper respiratory symptoms, are a risk for asthma 45, 4647-49. PVCM can produce 
symptoms that mimic asthma 50, 51 and can exist in isolation or co-exist with asthma; work-related or 
irritant-induced vocal cord dysfunction has also been described 52, 53. Irritant induced vocal cord 
dysfunction has been described in WTC-exposed populations 54. PVCM can complicate treatment 
decisions and lead to overuse of medications and despite its importance, PVCM can be difficult to 
diagnose 55. The presence of isolated or concurrent PVCM in the WTC EHC may account for persistent 
respiratory symptoms despite high dose ICS/LABA therapy. Thus we propose a standardized 
evaluation of patients to assess for presence of continued upper respiratory tract symptoms.  
• PTSD/Anxiety/Depression. High rates of post traumatic stress (PTSD), anxiety and depression are well- 
described in WTC-exposed populations 21, 56 including ours 27. A strong association between PTSD and 
chronic medical illnesses has been suggested by several studies 57-65. Thus the presence of PTSD and 
anxiety may aggravate the symptoms of asthma and make the disease more difficult to treat.  
• GER. Asthma is associated with symptomatic and asymptomatic gastroesophageal reflux (GER) 66 and 
symptoms of asthma may overlap with those of GER 67. Proposed mechanisms include the potential for 
microaspiration, as well as reflex-mediated effects of acid on the upper airway. However, in studies that 
included ambulatory esophageal pH-monitoring studies, we recently showed that treatment of 
asymptomatic GER did not influence asthma control 68, 69 that asymptomatic GER may not be a frequent 
cause of poor asthma control. In addition, proton-pump inhibitors failed to improve methacholine 
reactivity 68. Because of the prevalence of symptoms consistent with GER our population 26, we will 
assess whether GER symptoms are a risk for ULRS. 
New concepts in uncontrolled or “difficult to treat” asthma. 
To understand the refractory nature of these LRS, we use the World Health Organization’s (WHO) approach 
to severe asthma in which these patients were characterized as “difficult-to-treat” asthma  or “severe 
therapy-resistant” 70, 71. Possible reasons for uncontrolled asthma include: 
• poor adherence with recommended medication regimens,  
• treatment-resistant lung physiology and inflammation,  
• the presence of co-morbid conditions, or environmental factors that aggravate symptoms 71-74.  
We will confirm adherence and re-evaluate lung function to further characterize the underlying disease 
physiology including novel measurements of distal airway disease and BHR, lung inflammation to 
characterize disease process, and targeted co-morbid conditions.   
INNOVATION  
This study will fill an important knowledge gap for understanding and potential treatment of persistent 
LRS resulting from an environmental exposure. The measurements of distal lung function and 
inflammatory markers will provide novel information that will inform studies of asthma-like lower 
respiratory symptoms in these populations. The findings can be used to help guide therapy for this 
population including guidance for a subsequent reduction in the use of corticosteroids. Characterization of 
the underlying physiology, inflammatory response and co-morbid conditions in these patients has the 


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potential to provide information that can be used for other populations with airway disease, including 
those exposed to other environmental insults.  
 
Study Design 
Characteristics of the Research Population 
Number of Subjects 
Screening 300 subjects to enroll 200 subjects.  
Patients will be recruited from the WTC EHC population using block stratification a priori to obtain a 
representative sampling of the monitoring population (i.e. 5 patients with recent monitoring visits, 5 
patients with monitoring visits > 1 year previously). The sampling will not be stratified by race/ethnicity, 
age, and exposure but these variables will be adjusted in statistical analyses. We anticipate that we will 
telephone 300 patients for our final enrollment of 200 patients for the study.  
 
Gender of Subjects 
We intend to enroll both women and men in the approximate distribution of our clinic – 48% women, 52% 
men.  
Age of Subjects 
We will enroll patients from our adult clinic which includes patients > 18 years of age (NIH definition of 
children is < 21) and will include patients up to age 75. Above age 75, there are few normal values for lung 
function testing.  
Racial and Ethnic Origin 
We will enroll subjects with the race/ethnic distribution of the data from our monitoring results in the 
WTC EHC clinic, which is approximately 40% Hispanic, 20% Black. 6% Asian. 
 
Inclusion Criteria 
Age > 18 years and <75 
Meet criteria for WTC EHC enrollment 
Onset of LRS after 9/11/01 
Persistent LRS at chart review of WTC EHC 
Monitoring visit 
 
Pre-bd FEV1 within normal limits at chart 
review of WTC EHC Monitoring Visit 
< 5 p-y tobacco 
Not current smoker 
Asthma Control Test Score ≤ 19 at chart 
review of WTC EHC Monitoring Visit 
Normal CXR 
 
 


S13:00448 Protocol, Version 12. 31.2014 
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Exclusion Criteria 
Age < 18 years and Age ≥75 
LRS or asthma history pre 9/11/01 
No persistent LRS 
pre-bd FEV1 below the lower limit of normal (NHANES) 
> 5 p-y tobacco 
Current smoker 
Asthma Control Test Score ≥20 
Abnormal CXR or parenchymal changes on HRCT 
 
Uncontrolled major chronic illness (DM, CHR, cancer,mental health) 
History of significant non-WTC occupational or environmental exposure 
Allergy to study drug 
Pregnancy, lactation or plans to become pregnant 
Chronic oral corticosteroids 
High risk of fatal or near-fatal asthma within previous 2 years 
Other lung disease (IPF, sarcoid etc.) 
 
Vulnerable Subjects 
N/A 
Methods & Procedures 
Methods & Procedures 
SA1.a To test whether a three month treatment with combined high dose inhaled corticosteroids (ICS) and 
long acting bronchodilators (LABA) results in improved LRS. 
Trial Scheme. Subject recruitment and a trial scheme visit schedule is shown in Fig 1. 
Database Pre-screening. Pre-screening will be used for initial subject recruitment. Dr. Reibman is a 
member of the WTC EHC Data Center, and will work in collaboration with the WTC EHC Data Center 
(collaboration letter included). Only patients who have agreed to be re-contacted will be included. 
Information on symptom frequency will be obtained from data from the standardized “monitoring” visit. 
Patients with persistent LRS will be invited for an Initial Visit (V1).  
Definition of persistent LRS. We define 
“persistent LRS” based on definitions for the 
NIH asthma guidelines as LRS that occurs> 
2x/week in the month preceding the monitoring visit. LRS will include: wheeze, shortness of breath at rest 
or with mild exertion, or chest tightness. These criteria for inclusion will be confirmed during V1 with a 
repeat questionnaire.  
Fig. 1. Trial visit scheme. 


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8 
 
Sampling strategy for screening and enrollment in V1. Patients will be recruited from the WTC EHC 
population using block stratification a priori to obtain a representative sampling of the monitoring 
population (i.e. 5 patients with recent monitoring visits, 5 patients with monitoring visits > 1 year 
previously). The sampling will not be stratified by race/ethnicity, age, and exposure but these variables 
will be adjusted in statistical analyses. We anticipate 
that we will telephone 300 patients for our final 
enrollment of 200 patients for the study.  
Inclusion/Exclusion 
criteria. 
Detailed 
inclusion/exclusion 
criteria 
for 
subject 
identification for potential 
 enrollment include: 
• Onset of LRS after 9/11/01 
• Presence of LRS > 2x/week in the month 
preceding the monitoring visit at chart 
review of the WTC EHC Monitoring visit and 
confirmed in V1 
• Absence of abnormal CXR or other lung 
disease 
• ACT score ≤ 19 at monitoring visit 
Detailed exclusion criteria for potential enrollment 
include: 
• Presence of abnormal CXR 
• Presence of other lung disease (e.g. ILD, 
sarcoidosis) 
• Current or > 5 p-y tobacco use 
• ACT score≥ 20 at monitoring visit  
A study scheme and procedure chart is shown: 
Telephone screening visit (SV)  
Patients with persistent LRS will be identified from 
the WTC EHC data base and will be contacted by 
telephone or in person. Study will be described and 
interest in study will also be determined.  
Enrollment visit (V1) 
Control status will be assessed with the Asthma 
Control Test (ACT), a symptom-based validated 
instrument 76, 77.. Questionnaires to assess detailed 
specific respiratory symptom frequency, current 
environmental exposures, and severity and co-
morbid conditions of PTSD/depression/anxiety will be administered. The Modified Medical Research 
Council (MMRC) dyspnea scale will be completed to assess degree of dyspnea.  Baseline FeNO (fractionated 
exhaled Nitric Oxide) and pre and post bronchodilator (bd; 360 mcg albuterol) spirometry and IOS will be 
obtained.  
Patients will treated in the following manner based on assessment at V1: 
• 
Patients who have uncontrolled LRS (ACT < 20) at time of this visit will be provided with 
study Advair for a total of 3 months.  
Screening 
V1 
(enrollment) 
V2 
V3 
V4 
 
Time (weeks) 
1
4
8
12
Consent 
X
Inclusion/exclusion 
X 
 
X
Study review 
X 
 
X                      
 
 
 
ACT 
X                      x 
x 
X 
Physical Exam 
X
FeNO 
X
 
 
X 
Spirometry (pre/post bd) 
X
X
IOS (pre/post bd) 
X
X
Adherence counseling 
X
X
X
Daily diary review 
X
X
X
Medication distribution 
X
X
X
Classification confirmation 
X 
 
X
Co-morbidMedical 
Questionnaire (GSAS,SSS) 
 
                         
X 
Vocal Handicap Index 
 
X
Respiratory 
questionnaire (ASUI) 
 
X
 
X
MentalHealth 
Questionnaires(SF12V2, 
PHQ,PCL) 
 
x 
 
 
 
x 
MMRC Dyspnea Scale 
 
 
X                      
 
 
X 
VCD assessment 
 
X
MCT  
 
 
X
 
Pregnancy test 
X
X
Blood 
X 
 
 
AE screen 
 
X
X
X
Leicester Cough Questionnaire  
 
X 
 
Urine Sample for Cotinine 
 
 
X 
 
6 minute walk test 
 
 
x 
 


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9 
 
• 
Patients who have uncontrolled LRS at V1, but do not fit criteria for Step 3,4 or 5 asthma 
therapy according to NIH EPR III asthma guidelines will be deferred from the study until 
they have been seen by their physician and tried on ICS therapy. 
• 
Patients who had symptoms at monitoring visit but are now controlled at V1 will be asked 
to continue their current treatment (or no treatment) and will continue with the study. They 
will not be provided with any medications.  
 
Study medication will  be provided as open label high dose ICS/LABA diskus (fluticasone /salmeterol; 
500/50 mcg; 1 inhalation twice daily, or MDI 230/21, 2 puffs bid) for a 1 month period. Inhaler training 
and adherence counseling will be performed. Patients will be instructed to maintain a daily diary. 
Adherence visit (V2) Patients will return for a monthly visit. At this visit the study will be reviewed, inhaler 
technique reviewed, and adherence counseling administered. Notation of the counter denoting actuation 
of the ICS/LABA diskus will be made to assess adherence.  Daily diary will be reviewed. Patients will be 
queried for any adverse effects. Questionnaires to assess co-morbid conditions of chronic rhinosinusitis, 
and gastroesophageal reflux (GER) will be administered as well as the ACT to assess for control status 
Adherence visit (V3) This visit will be similar to V2, however, a methacholine challenge test with lung 
volumes and oscillometry will also be performed on all patients. Patients will complete the Leicester Cough 
Questionnaire at Visit 3. Urine will be obtained for cotinine measurements. as well as the ACT to assess for 
control status 
Classification visit (V4): After 3 months, patients will return for their Classification. At this visit, medication 
use will be reviewed by noting the medication actuations, and ACT and disease-specific questionnaires for 
asthma control (ASUI) will be completed 78, 79. Screening instruments for post-traumatic stress disorder 
(PTSD), depression and anxiety will be completed. Blood will be obtained for total and allergen specific IgE, 
peripheral eosinophil measurements, and measurements of serum periostin and C-reactive protein. FeNO, 
pre and post BD spirometry and IOS will be performed. Patients will complete a 6 minute walk test. Patients 
will also undergo laryngoscopy and vocal cord assessment If patients are unable to complete the vocal cord 
assessment on the same day as V4, they will be asked to return for a separate visit within two weeks of the 
end of study (Day 76-90) and will be compensated $100 for this additional time and effort.   
Control Classification. Patients will be classified as ULRS or CLRS based on the ACT score obtained at V4.  
Specific Aim 2. To test the hypothesis that discrete measures of lung physiology are associated with 
patients in the WTC EHC with URLS compared to CLRS.  
Preliminary data pertinent for SA2. 
Lung function in WTC EHC. We previously described characteristics of an initial group of participants (n = 
1898) in the Bellevue WTC EHC 26. Although diverse in gender, ethnicity, socioeconomic status, and types 
and degree of WTC exposure, the symptoms and clinical syndromes in this population are similar to those 
of responder cohorts with dyspnea on exertion (67%), cough (46%), wheeze and chest tightness (25%) 
the most frequent symptoms. Few (31%) of participants had any abnormality on spirometry, with the most 
common abnormality being a low forced vital capacity (FVC); a much smaller group had reduced forced 
expiratory volume in 1 second (FEV1) consistent with classic obstruction. In collaboration with the NYC 
DOH, we also described lung function in persistently symptomatic enrollees in the DOH WTC Health 
Registry 23, 80, suggesting that symptoms are related to acute and chronic WTC exposures. Moreover, we 
demonstrated increased rates of abnormal IOS measurements, consistent with distal or small airway 
disease 80. We also found abnormal IOS measurements in members of the WTC EHC with normal 
spirometry, and an association with symptom severity 28. Most recently, we suggested that IOS 
measurements during MCT can provide additional information about BHR and symptoms 32.  
Longitudinal improvement in spirometry but not IOS. Examination of longitudinal spirometry 
measurements in the WTC EHC suggests that many spirometric parameters improved over time 30. A mixed 


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effects model showed a small but significant improvement in FEV1 and FVC even in patients with a normal 
spirometry pattern at the time of enrollment, with greatest change in non-smokers. The increased access 
to health care services including free medication was one plausible explanation for the observation. 
Recently, we evaluated longitudinal measurements in IOS parameters 81. Surprisingly we failed to 
document an improvement in IOS measurements. These data raise the provocative question whether 
despite improvement in larger airways, patients have continued distal airway abnormalities that 
account for persistent LRS.  
SA2.a To test whether bronchial hyperresponsiveness (BHR) is associated with the status of ULRS and 
CLRS by comparing rates of BHR in patients with ULRS and CLRS.   
Bronchial hyperresponsiveness (BHR). BHR is often used as a diagnostic tool and is consistent with, but 
not diagnostic of, asthma 29. Use of ICS may reduce BHR, but may not normalize the response 82-84.  BHR 
and airway inflammation can therefore remain positive even in those with well-controlled asthma 85 and 
measures of BHR can be used to optimize treatment and control 86. Routine BHR testing was never part of 
the WTC EHC or WTC Worker program and thus pre-treatment studies are not available for these 
populations. The possibility exists that patients with ULRS may have persistent BHR despite therapy. We 
will therefore compare rates of BHR in patients with ULRS and CLRS. All patients will undergo BHR during 
V3, when they have received 2 months of study therapy, to encourage patient return and to streamline the 
number of visits. For consistency, patients will be asked to withhold morning medications. They will then 
undergo a methacholine challenge test (MCT) as per ATS recommendations 87 and recent review 29. 
Increasing doses of methacholine will be administered with a 2 minute tidal breathing protocol up to a 
maximum dose of 16mg/ml. The calculated provocative concentration that results in a 20% fall in FEV1 
(PC20) will be used to determine the degree of BHR. We will use the tidal breathing technique as it is more 
accurate and sensitive than one using deep inspiration 29. 
SA2.b To test whether measurements of airflow and lung volume (FEV1, FVC, FEV1/FVC, RV/TLC) and of 
small airway dysfunction (IOS) are associated with ULRS and CLRS status.  
Spirometry/Lung function. To determine whether spirometry measurements and bronchodilator (bd) 
response are associated with ULRS, patients will undergo pre and post-bd (360 mcg albuterol sulfate) 
spirometry at V1 and V4. For consistency, patients will be asked to withhold morning medications. 
Spirometry will be performed according to American Thoracic Society/European Respiratory Society 
standards (Vmax, CareFusion, Yorba Linda, CA) 88. Data collected will include FVC, FEV1 and FEV1/FVC. 
Predicted values will be derived from National Health and Nutrition Education Survey (NHANES III) 89, 90. 
Lung volumes will be assessed by plethysmography, and pulmonary diffusion will be measured using the 
single breath technique.  Data collected will include functional residual capacity (FRC), total lung capacity 
(TLC), residual volume (RV) and the pulmonary diffusing capacity for carbon monoxide (DLCO).  The 
measured DLCO will be adjusted for the presence of anemia based on the measured hemoglobin level.  All 
tests will be conducted in accord with the American Thoracic Society/European Respiratory Society 
recommendations. 
Distal or small airway function. IOS is a non-invasive tool that measures the relationship between pressure 
waves applied externally to the respiratory system and the resulting respiratory airflow. IOS can provide 
information about the distal airways. We previously demonstrated an association of LRS with 
measurements of distal airway dysfunction using IOS 28, 33, 80. We will now test whether ULRS is associated 
with elevated measurements of distal airway function and compare IOS measurements obtained in V4 in 
patients with ULRS and CLRS. IOS maneuvers (Jaeger Impulse Oscillation System) will be performed in 
accordance with European Respiratory Society recommendations 91 and as described 80. Maneuvers will 
be performed during tidal breathing with patients in the seated position, with a nose clip in place, 
supporting their cheeks with their hands. A minimum of three trials, each lasting 30 seconds, will be 
performed. Only data from trials with constant tidal volume and coherence >0.70 at 5Hz and 0.85 at 10Hz 
will be analyzed 33, 92.  Reproducibility between trials (variability <10%) will be required. IOS data will 
include resistance measured at an oscillating frequency of 5 Hz (R5) and 20 Hz, which can identify an 


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increased resistance in the system even when spirometry is normal. Frequency dependence of resistance 
(FDR) calculated as the difference between resistance at 5 Hz and 20 Hz (R5-20) provides a measure of non-
uniformity of airflow distribution, which may reflect regional functional abnormalities in the distal airways 
93-95.Analyses of IOS data will be adjusted for covariates including BMI as previously described 28, 80. 
Specific Aim 3. To test the hypothesis that inflammatory markers associated with airway disease 
are increased in patients with ULRS compared to CLRS in the WTC EHC  
Preliminary data pertinent for SA3. 
Elevated circulating eosinophils in WTC EHC patients with wheeze.  
We recently reported elevated levels of peripheral eosinophils in a cohort of WTC EHC patients 96. Patients 
who met inclusion criteria (n = 1508) had a mean age of 47 years with diverse race/ethnicity. A larger 
percentage of those with wheeze had elevated peripheral eosinophils compared to those without wheeze 
(21 vs. 13%, p<0.0001). Individuals with elevated peripheral eosinophils were more likely to have airflow 
obstruction on spirometry (34% vs. 14%, p = 0.0003). We also recently found elevated peripheral 
eosinophils in phenotypic subgroups of asthmatics supporting our ability to identify heterogeneity in 
asthma 97. 
Elevated levels of FeNO in WTC EHC patients.  
We obtained fractional exhaled nitric oxide (FeNO) measurements on individuals from our WTC clinic who 
presented with lower respiratory symptoms (n = 100), patients with asthma but without WTC exposure (n 
= 23), and a control group without asthma (n = 11) for a pilot study. Mean FeNO was elevated in individuals 
with WTC-related asthma compared to controls (31 ppb vs. 20 vppb p=0.001. These data show our ability 
to measure FeNO and suggest that levels are increased in patients with WTC-related asthma. 
Elevated CRP is associated with reduced lung function. We evaluated peripheral C-reactive protein (CRP) 
as a measure of systemic inflammation in a sequentially enrolled cohort of WTC EHC patients (n = 208). 
Exposure categories (local workers, clean-up workers, residents) were associated with normal and 
elevated CRP levels (p = 0.01). Smokers had a larger portion of elevated CRP than non-smokers (p < 0.05), 
and body mass index (BMI) was significantly higher among the high CRP group (p < 0.001). FEV1 and FVC 
were lower among the high CRP group (p < 0.02, p < 0.04). Multiple regression analysis confirmed that 
log(CRP) values were inversely correlated with % predicted FEV1(p = 0.009) and positively correlated with 
IOS measurements (logR5; p = 0.02) and logAX; p = 0.005) after adjustment for logBMI. These data suggest 
a role for systemic inflammation in patients in the WTC EHC. 
SA3.a Compare levels of FeNO in patients with ULRS and CLRS. 
FeNO. Measurement of FeNO is simple, safe and reproducible, and higher FeNO levels are associated with 
eosinophilic inflammation and responsiveness to corticosteroids 42. We will measure FeNO at V1 and again 
at V4 with the handheld NIOX MINO (Aerocrine; Stockholm, Sweden). Subjects will avoid eating or drinking 
at least 1 hour before testing, and measurements will be taken before spirometry. FeNO results will be 
reported for an exhalation flow rate of 50 mL/s, and measurements will be expressed in part per billion 
(ppb). Our initial analysis will compare FeNO levels between ULRS and CLRS at V4.  
SA3.b Compare levels of circulating biomarkers associated with a Th2 inflammatory response in patients 
with ULRS and CLRS.  
Atopic status. Atopic status is an important phenotype for asthma with implications for treatment 98. The 
general rates of allergen sensitization in WTC-exposed populations are unknown. Consistent with recent 
recommendations for asthma biomarkers, we will characterize atopic status of ULRS and CLRS using 
quantitative serologic measures of total IgE and individual allergen-specific IgE antibodies for allergens 
significant for the Northeastern United States obtained from a commercial laboratory (Pharmacia 
ImmunoCAP assay; Quest Diagnostics; Teterboro, NJ). An allergen-specific IgE level > 0.35 kilo-
international units (kIU)/L will be considered positive. Atopy will be defined as the presence of at least one 


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elevated allergen-specific IgE. Comparisons between total IgE level, atopy and presence of indoor or 
outdoor allergens will be made between ULRS and CLRS. 
Eosinophils. Analysis of blood and sputum eosinophils can provide useful information to characterize a 
study population for observational studies 42. Our preliminary data suggest elevated circulating 
eosinophils in WTC EHC patients with wheeze reflecting a Th2, IL-13 inflammatory pathway. We will 
perform automated complete blood cell counts on all patients during V4. Data will be compared as 
complete eosinophil counts as well as dichotomized to high and low % eosinophils in ULRS vs. CLRS.  
Periostin.Periostin is a matricellular protein expressed by mesenchymal cells and airway epithelial cells 43, 
99, 100. Elevated epithelial and serum levels of periostin are associated with treatment success with an anti-
IL-13 monoclonal antibody 39. We will measure serum periostin in blood obtained during V4. For 
quantitative determination of human periostin (OSF-2) between ULRS and CLRS, we will use a 
commercially available ELISA kit (Adipobioscience, Santa Clara CA) with a range of 31 – 2,000 ng/mL.   
Future inflammatory markers. Blood samples obtained at V4 will also be saved as serum/plasma for future 
evaluation of potential inflammatory markers in the CTSI biorepository. 
Specific Aim 4. To test the hypothesis that increased rates of co-morbid conditions are associated 
ULRS compared to CLRS. 
Preliminary data for SA3.  
Coexistence of PTSD symptoms and persistent respiratory symptoms. Since the inception of the WTC EHC, 
our clinical screening has included evaluation for PTSD, depression and anxiety using the PTSD Checklist 
and the Hopkins symptom checklist. The PTSD Checklist (PCL) is a 17 item self report score based on DSM-
IV symptoms of PTSD and has been validated for screening, diagnosis and monitoring of treatment of PTSD 
in military, civilian, and event specific contexts 101. The Hopkins symptom checklist-25 is a widely 
employed assessment tool for depression and anxiety symptoms 102. Although insufficient to make formal 
psychiatric diagnoses; these elevated symptom scores can be used to asses for probable PTSD, depression 
and anxiety. In our analysis of our initial patients enrolled for physical symptoms, (n = 1825), we described 
high rates of probable PTSD, anxiety and depression. Elevated mental health scores were associated with 
LRS but not with lung function.  
SA4.a Compare rates of PTSD, anxiety or depression in ULRS and CLRS. 
PTSD/depression/anxiety. ULRS symptoms could be complicated by co-existent mental health conditions. 
We will administer validated tools to assess PTSD symptoms, depression and anxiety at V1 and V4 using 
the Patient Health Questionnaire (PHQ).  We will also use theSF12v2, a validated instrument that contains 
12 questions that cover social activity limitations, mood and practical and existential concerns. Because 
these illness are often co-related, we will assess for the association of ULRS with elevated scores for PTSD, 
anxiety/panic and depression individually using the Wilcoxon rank test and with logistic regression 
models. The logistic regression model can estimate the effects the psychiatric comorbidity scores jointly 
and evaluate the significance adjusting the presence of others. 
SA4.bCompare rates of rhinosinusitis and paradoxical vocal cord motion (PVCM) in patients with ULRS 
and CLRS.  
Rhinosinusitis symptoms. Sinusitis and rhinitis often co-exist with uncontrolled asthma. Diagnosis of 
chronic rhinosinusitis is difficult, and guidelines recommend symptom-based criteria 108, 109. Although 
imaging is also recommended by some, computerized tomography is expensive and results in a radiation 
dose. Validated instruments to screen for chronic rhinosinusitis have recently been developed. We will use 
a 5-item questionnaire at V4 to assess the presence of chronic rhinosinusitis disease 110. This instrument 
is highly sensitive and specific for diagnosing chronic sinonasal disease with a cutpoint of 1 (experiencing 
each symptom an average of one to four times per month).  


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Nasal endoscopy and analysis for PVCM. Nasal endoscopy and analysis for PVCM will be performed during 
V4 in all patients at the New York University Langone Medical Center (NYULMC) Voice Center, located 
adjacent to Bellevue Hospital. Patients will be escorted to the NYULMC Voice Center where they will 
undergo evaluation by an otolaryngologist. Flexible nasal endoscopy will be performed and scored as: 
discharge (0 = absent, 1 = clear, 2 = purulent), mucosal inflammation/scarring (0 = absent, 1 = mild, 2 = 
severe) and the presence of polyps (0 = absent, 1 = middle meatus, 2 = beyond middle meatus) 110. In 
addition, examination and evaluation for findings associated with GER will be performed during 
laryngoscopy. 
Paradoxical vocal cord motion (PVCM) refers to inappropriate adduction of the vocal folds during 
respiration and is often misdiagnosed as refractory asthma 111 and PVCM may mimic asthma or co-exist 
with asthma 71. The NYULMC Voice Center is equipped to evaluate patients with WTC asthma for PVCM as 
an isolated condition, or as a co-morbid condition that might cause symptoms despite adequate asthma 
therapy 112, 113. Laryngoscopy with videolaryngostroboscopy to exclude other more subtle neurological 
abnormalities is currently the most widely accepted standard for the diagnosis of PVCM 112. However, 
because PVCM occurs episodically, failure to visualize the abnormal vocal fold motion on a single exam 
cannot exclude the disorder. In clinical practice, the diagnosis is frequently established based on a 
constellation of historical details (laryngospasm, voice pattern abnormalities) and laryngoscopic findings. 
Our evaluation will include a history and physical exam and administration of the Voice Handicap Index 10 
114. Videolaryngostroboscopy with provocation will be performed at V4. All patients will be assessed at 
baseline for PCVM. If subjects demonstrate PCVM exam findings, the patient will be labeled as “definite 
PCVM” and the scope will be removed. If PCVM features are not noted at baseline, a provocation test may 
be performed. Patients may be exposed to challenges that are designed to bring out symptoms. These 
challenges include different scents, including perfume or cleaning products. In addition, an exercise 
challenge may be performed. The patient may be asked to exercise by walking in a hallway or up and down 
stairs in order to try to mimic symptoms. A final assessment will be performed by videolaryngostroboscopy 
to determine presence of PCVM and the scope will be removed. Each patient will be given a designation of 
“no PVCM,”  “probable PVCM” or “definite PVCM,” based on the comprehensive evaluation and rates 
compared between ULRS and CLRS. 
SA4.cCompare rates of GER symptoms in patients with ULRS and CLRS.  
GER. We have a high rate of GER symptoms in our population, and these symptoms can affect LRS. We will 
use a validated questionnaire to gauge the presence or absence of symptoms due to GER via the 
Gastroesophageal Reflux Disease Symptom Assessment Scale (GSAS), which measures both the number 
and the severity of symptoms. 115We will evaluate the rates of GER symptoms between URLS and CLRS.  
 
Data Analysis and Data Monitoring 
Sample size estimation 
Our primary outcome will be the rate of LRS and CLRS after the 3 month adherence period (SA1). We base 
our sample size and recruitment on our initial analysis of the WTC EHC monitoring in which 88% of 
patients who had ever received ICS or ICS/LABA had an ACT score of < 19. We assume however, that many 
of these patients were either no longer using medication at the time of the assessment, were on minimal 
dose, or were non-adherent. Thus we predict by V4 that we will have a 60% rate of ULRS and a total of 200 
patients would yield 120 patients who will fit criteria as ULRS and 80 as CLRS. To take into account 
potential screen failures and dropouts, we will approach 300 patients initially to obtain the total sample 
size of 200. We will include drop-outs in our intention to treat analysis as these patients can be considered 
for baseline analysis.  
For categorical endpoints, such as BHR, PTSD and PVDM, the sample sizes of 120 in ULRS group and 80 in 
CLRS group will achieve 80% power to detect an odds ratio of 2.08 at significance level of 0.05, assuming 
that the rate of disease is 30% in the CLRS group. A logistic regression of the ULRS vs. CLRS on a continuous, 


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normally distributed variable (such as depression score or log-FeNo) with a sample size of 200 
observations will achieve 80% power at a 0.05 significance level to detect an OR of 1.498 for 1- standard 
deviation (SD) difference in the continuous covariate. 
Statistical analysis of the data. To compare variables between ULRS and CLRS groups, we will use the 
Chi-square test for categorical variables (e.g. the presence of BHR) and the nonparametric Wilcoxon rank 
test for continuous variables (e.g. depression score, CRP level). Logistic regression models will be used to 
evaluate the association between the disease status (ULRS vs. CLRS) and the variables under hypothesis 
adjusting for other demographic variables and confounders such as age, gender, BMI, and WTC exposures 
(obtained from initial questionnaires). Odds ratios (ORs) of ULRS in relation to risk variables will also be 
estimated and confidence interval and statistical significance will be reported. In exploring the shape of the 
effect of continuous variables, log transformation may be conducted to improve the fit of the model and 
the interpretation of results if a skewed distribution is present, or categories defined by quartiles of 
continuous variables will also be used in logistic regression. To identify joint effects of multiple important 
variables in the logistic regression models, we will use the likelihood ratio test and Akaike's Information 
Criterion (AIC) for model evaluation. The likelihood ratio test is a standard approach to compare nested 
models, and the AIC is used for comparing non-nested models.  
Data Storage and Confidentiality  
Data will be kept in a secure database in the NYU CTSI server. Any paper data will be maintained in a locked 
file in a locked room. Data will be available to the data manager, clinical coordinator coder and the PI for 
routine verification of case report forms and de-identified data will be available to study personnel.  
 
Blood Sample Storage and Use 
Samples will be kept according to CDC/NIOSH regulations for sponsored projects. Blood samples obtained 
as part of the standard protocol will be tested for markers of inflammation. These markers include, but are 
not limited to, proteins such as periostin, eotaxin C-reactive protein, and others that may be identified as 
important markers of inflammation. 
For the duration of the study, and for a period of up to 3 years after the conclusion of the study, blood 
sample specimens obtained during Visit 4 will be stored in the NYU-CTSI BioRepository. Only members of 
the study team will have access to these samples and sample information. Samples will be labeled with the  
patient study identification (coded number) information only, not personal health information.  The 
investigator will ensure that patient anonymity is maintained. Patient study identification information will 
be stored in password-protected computers.  
Sample storage for future use 
Additional blood samples that are obtained by patients who have given this optional consent will be stored 
in the NYU-CTSI BioRepository indefinitely and marked with the study patient indentification (coded 
number) information only.  This label will not contain personal health information (PHI). Only members of 
the study team will have access to these samples and sample information. Future testing will aim to better 
understand asthma and inflammatory markers that may be associated with the disease. 
 Samples will only be shared with outside investigators through a signed Materials Transfer Agreement 
(MTA). Patient health information linked to the samples will only be shared after the outside investigators 
have received Insitutional Review Board approval for their studies.  Results of testing on the blood samples 
will not be shared with patients. Subjects will be allowed to withdraw their samples at any time, at which 
point they will be destroyed and removed from any future analysis. Storage of samples for future use is not 
required for participation in the study.  
 
Data Safety Monitoring Plan 


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All adverse events including unanticipated effects of the study drug, lung function studies or vocal cord 
assessments and protocol violations will be collected.  Serious adverse events such as unanticipated 
urgent care visits other than for asthma exacerbations that the investigator thinks might be due to study 
intervention will also be collected.  
Adverse events and serious adverse events will be reported on case report forms completed by the 
research staff and reported immediately to the Principle Investigator, Dr. Reibman,. The monitoring 
entity for this study, Dr. Reibman,and co-investigators Dr. Kazeros and Dr. Caplan-Shaw ,will review the 
data and the circumstances of the event to ensure that any required changes to the protocol or 
procedures are made and submitted to the IRB. 
The monitoring entity (Dr. Reibman, Dr. Kazeros, Dr. Caplan-Shaw) will meet every 6 months to ensure 
protocol compliance and to review any adverse events. Documentation of these meetings and safety 
summaries will be maintained in the regulatory binder and reported to all regulatory bodies as required.  
Throughout the study,  Drs. Reibman, Kazeros and Caplan-Shaw will  monitor the participants for adverse 
events. Events determined by the Principle Investigator to be unanticipated problems  involving risk to 
subjects or others will be reported by the PI to the IRB within 5 working days as per  NYUSOM IRB 
regulations. Other adverse events that the PI determines are not unanticipated problems involving risks 
to subjects or others will be reported by the PI to the IRB  at the time of continuing review. 
Any serious adverse events will result in a delay in the continuation of the study pending review of the 
Serious Adverse Event 
 If upon review, trends are reported from this protocol that indicate a risk to subjects or others, the 
protocol will be modified in accordance with the research plan and patient safety regulations to minimize 
any adverse events that are occurring in the study. Protocol changes will not be made prior to IRB 
approval unless necessary to eliminate apparent immediate hazards to the research subjects  
Data Monitoring 
All research staff will be trained in Good Clinical Practice, IRB regulations and HIPAA regulations and will 
be responsible for data entry. Data will be collected following the consent process and will be entered in 
the secure NYU CTSI Redcap system within 3 days of each visit by the research staff. Data will be entered 
into the secure CTSI Redcap program by research staff. All primary source documents will be kept in a 
locked cabinet in a locked room. Protocol compliance and data verification will be performed  by the 
investigators Reibman, Dr. Kazeros and Dr. Caplan-Shaw,  every 6 months. Random audits will be 
performed on every 10th primary source document and every 10th database entry to ensure data accuracy 
and compliance with the protocol.  
 
Risk/Benefit Assessment 
Protection against Risk 
The following are risks and discomforts that patients may  experience during their participation in this 
research study. Study staff will be trained to report adverse events to the study doctor so that risks to 
patient health will be minimized. 
We will ask you to withhold all your inhaled medications for 8 hours before the study. The withholding of 
your medications may allow your breathing to become worse. Should this occur, we will advise you to 
restart your medications and we reschedule your appointment.  
Spirometry and oscillometry. Spirometry is a standard test performed on all patients with asthma or 
breathing difficulties. During the study, we will ask you to breathe hard. There is a risk that this could make 
your asthma worse. Should this occur, we will administer a bronchodilator (albuterol sulfate by metered 
dose inhaler) to treat the asthma. During the spirometry examination we will administer albuterol sulfate 


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by a metered dose inhaler or nebulizer (180 - 360 mg) and then perform the spirometry maneuvers again 
for a "post bronchodilator study". This is a standard procedure for patients with asthma. Albuterol sulfate 
is a bronchodilator used by almost all patients with asthma. Some people find that the inhalation of this 
medication makes them jittery and may make their heart beat faster. Should this occur, these symptoms 
will resolve on their own within a few hours. For the oscillometry testing we will ask you to breathe quickly. 
There are no known risks to this. 
Exhaled Nitric Oxide. For the measurement of exhaled nitric oxide we will ask you to breathe slowly or to 
breathe regularly into a tube. There are no known risks to breathing into a tube unless you are allergic to 
latex. Please let us know if you are allergic to latex.  
Inhaled fluticasone proprionate and salmeterol (Advair Diskus). This is a standard medication used for the 
treatment of asthma and you may even be taking this medication before the study. We are treating you 
with this medication because you have continuing symptoms and we are providing you with a short course 
(3 months) of treatment, which reduces the possibility of many of these side effects. This medication 
consists of two medications: an inhaled corticosteroid and a long-acting beta2-adrenergic agonist (LABA). 
The possible risks mentioned in the Physicians’ Desk Reference include: 
Localized infections: Candida albicans infection of the mouth and throat may occur. To prevent this we 
advise patients to rinse their mouth following inhalation.  
Immunosuppression: Potential worsening of infections (e.g., existing tuberculosis, fungal, bacterial, viral, 
or parasitic infection; ocular herpes simplex) can occur with prolonged use. We use with caution in patients 
with these infections and will screen you for some of these questions by questionnaire before including 
you in the study.  More serious or even fatal course of chickenpox or measles can occur in susceptible 
patients.  
Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in 
susceptible individuals.  
Paradoxical bronchospasm (increase in asthma symptoms): We will discontinue Advair Discus and 
institute alternative therapy if paradoxical bronchospasm occurs.  
Patients with cardiovascular or central nervous system disorders: We will screen you with an 
electrocardiogram before enrolling you in this study and will use with caution because of beta-adrenergic 
stimulation.  
Metabolic effects: We will screen for many of these conditions in our initial evaluation but will be alert to 
eosinophilic conditions, hypokalemia, and hyperglycemia. We will screen for these coexisting conditions 
and use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and 
ketoacidosis.  
 
In addition, long-acting beta2-adrenergic agonists (LABAs), such as salmeterol, one of the active 
ingredients in ADVAIR DISKUS, can increase the risk of asthma-related death. Currently available data are 
inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma 
control drugs mitigates the increased risk of asthma-related death from LABAs but recommendations are 
now to prescribed LABA only with an inhaled corticosteroid, which is why we use the combination 
treatment.  
According to current recommendations for use, we only prescribe ADVAIR DISKUS for patients not 
adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or 
whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a 
LABA. We are including you in this study because your asthma or lower respiratory symptoms have not 
been controlled.  
 


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Methacholine Challenge. Methacholine Challenge will not be done in anyone with current asthma or 
breathing problems (such as asthma causing shortness of breath or chest discomfort or wheezing on the 
day of the test) or low lung function. We will also not do a methacholine challenge test if you already have 
a response to bronchodilator on your spirometry test. The methacholine challenge will only be done after 
a breathing test measures your lung function to be above 70%. Methacholine challenge will not be done in 
anyone with known allergy to methacholine.  There may be other reasons you cannot take this test.  The 
study doctor will discuss this with you. There are other medical conditions that are affected by 
methacholine. If you have such a condition, your study doctor must approve of you taking the test. 
This test is not likely to cause serious symptoms.  Some people have coughing or a tight sensation in their 
chest from breathing the methacholine, but it is usually mild.  About 1 in 4 subjects having this test notice 
some cough or shortness of breath and about 1 in 10 notices some wheezing. However, reaction to 
methacholine can include severe bronchoconstriction (such as a severe asthma attack) and loss in 
breathing function. If you develop an asthma episode during any of this procedure, we will stop the 
procedure and provide you with albuterol to improve your breathing. This will be provided by a physician 
involved in the study and you will be checked until your breathing has returned to its baseline.  
Blood test. Blood will be obtained by venipuncture.  
We will collect a blood sample that we will store 
and test for markers of inflammation as part of this research study. Blood will be drawn from a vein in the 
arm by usual venipuncture. The risks associated with a venipuncture procedure may include pain, bruising, 
swelling and/or infection where the needle is put in the vein. The total amount of blood to be drawn will 
be 30 ml (2 tablespoons). 
 
Vocal Cord Assessment. The vocal cord assessment involves the placement of a small camera through the 
nose.  This is typically done after numbing the nose with topical oxymetazoline (decongestant) and topical 
4% lidocaine delivered via an atomizer.  The risks are nasal bleeding and discomfort with the 
spray.  Allergies are very rare, but are possible. 
If you do experience a reaction to the medication, treatment will be administered until your condition 
returns to normal.  The placement of the camera can result in minor discomfort in the nose for about 1-2 
minutes (the typical length of the exam).  Rarely (<1% of the time), there may be some minor bleeding from 
the nose after the exam is complete.  This is usually limited and can be treated easily by the physician seeing 
you at the time. Patients may experience lower respiratory symptoms due to the presence of the 
laryngoscope and during the exercise challenge. 
The vocal cord assessment will take place at the NYU Voice Center,located at 345 East 37th Street, Suite 
306 New York, NY 10016. Patients will be accompanied by  study staff member to the NYU Voice Center. If 
a patient is unable to walk to the NYU Voice Center from Bellevue Hospital for any reason, a taxi will be 
provided at no cost to the patient. 
Protection Against Risks 
 
Protection against risks from specific procedures are described above. Furthermore, personnel will be 
appropriately trained in the identification and reporting of adverse events to the study doctor to 
minimize any potential risks or discomfort. If adverse events are reported, study will be delayed until the 
study doctor may determine the safest course of action, which may include withdrawal of the subject 
under monitoring of WTC EHC physicians.  If patients experience adverse mental health events, patients 
may be referred to WTC EHC mental health services. 
Potential Benefits to the Subjects 
There are potential benefits to the subjects.  This research study may change the treatment that the patient 
would otherwise receive.  Patients will be provided with a summary of results to bring to their health care 


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provider that will include the results of their breathing studies, methacholine challenge test, and vocal cord 
assessment. This may help the health care provider to guide his or her therapy. 
Investigator’s Qualifications & Experience 
Please see attached documents. 
Subject Identification, Recruitment and Consent/Assent 
 
Method of Subject Identification and Recruitment  
 
Pre-screening will be used for initial subject recruitment. Dr. Reibman is a member of the WTC EHC Data 
Center, and will work in collaboration with the WTC EHC Data Center (collaboration letter included). 
Only patients who have agreed to be re-contacted will be included. Information on symptom frequency 
will be obtained from data from the standardized “monitoring” visit. Patients with persistent LRS will be 
invited for an Initial Visit (V1). Patients will be recruited from the WTC EHC population using block 
stratification a priori to obtain a representative sampling of the monitoring population (i.e. 5 patients 
with recent monitoring visits, 5 patients with monitoring visits > 1 year previously). The sampling will 
not be stratified by race/ethnicity, age, and exposure but these variables will be adjusted in statistical 
analyses. We anticipate that we will telephone 300 patients for our final enrollment of 200 patients for 
the study. 
Patients will be asked if they would like to participate in the study by telephone and by written invitation. 
In order to further protect the privacy of patients, those who cannot be reached by telephone will be 
contacted at a later time (voicemail will not be utilized ). For those patients who will return to the WTC 
EHC for care, the WTC EHC physicians will also describe the study to the patient by the treating physician 
during an office visit.  For those without appointments during the recruitment period, the study will be 
described via a telephone screening. This will include the purpose of the study, and the risks and benefits 
of entering into the study. We will also explain what information will be collected prospectively, including 
questionnaire data and the procedures that will be administered during the study such as 
spirometry,oscillometry and methacholine challenge. Any questions that the subject will have will be 
answered.  If the patient decides to participate in the study, informed consent will be administered.   
 
Process of Consent 
 
If the patient decides to schedule a Visit 1, informed consent process will be administered. The informed 
consent will primarily be obtained by the clinical coordinator and will only be obtained by study staff 
listed on the protocol.  The informed consent document will include information, in lay terms, about the 
patient’s history of continued lower respiratory symptoms and use of inhaled corticosteroids, what it 
means, and what the purpose of the study is.  The informed consent is attached.  Informed consent will be 
obtained in CTSI behind closed doors to protect the patient’s privacy. Signed informed consent will be 
kept in a file in locked cabinets.  No other specific recruitment methods will be utilized. Patients will also 
have the right to withdraw from the study at any time point. If this is the case, they may contact the 
principal investigator, Dr. Reibman, 462 1st Avenue, Floor 7 Room 7N24, New Bellevue, New York, NY 
10016. 
 
Subject Capacity 
Patients with decisional making capacity will be provided informed consent. Informed consent will be 
explained to patients and patients will be assessed to see if they understand the study purpose, risks, 


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benefits, etc. Vulnerable subjects, including children, cognitively impaired, pregnant women, and 
prisoners will be excluded from the study.  
 
Subject/Representative Comprehension  
Patients will be provided with adequate time to complete the informed consent process. If patients 
decide they need additional time to consider their participation in the study and discuss the consent 
document with family, etc. the visit will be rescheduled.  Patients will be given opportunities to ask 
questions about the study and request additional information to make their decision.  
Debriefing Procedures 
None.  
Consent Forms 
Please see attached consent forms. 
Documentation of Consent 
Please see above.  
Costs to the Subject 
There is no cost to the subject for this study. All test and procedures preformed are covered by the study 
and will be at no expense to the participants.  
Payment for Participation 
Patients will receive fifty dollars for Visits 1 and 2 and one hundred dollars for Visits 3 and 4 to 
reimburse patients for their corresponding time and effort. Payment reflects the length of each visit. 
Patients who do not complete the visit or decide to withdraw their consent during the visit will still be 
reimbursed for their time without penalty. Reimbursements will be distributed as cash payments.