Assessing Inflammatory and Behavioral Pathways Linking PTSD to Increased Asthma Morbidity in WTC Workers
Phase: NA
Conditions: Asthma, PTSD
Sponsor: Icahn School of Medicine at Mount Sinai

Assessing Inflammatory and Behavioral Pathways Linking PTSD to Increased 
Asthma Morbidity in WTC Workers
Dr. Juan Wisnivesky
NCT04552301
Document Date: July 25-2016

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
1 
Revised  9/2/14 
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Brief Summary of Research (250-400 words): 
Asthma and post-traumatic stress disorder (PTSD) are the most common conditions in 
World Trade Center (WTC) rescue and recovery workers. A large number of WTC 
workers continue to report poor asthma control and impaired quality of life. Thus, asthma 
is a major cause of morbidity in this population. Several studies show a strong 
relationship between PTSD and increased asthma morbidity. PTSD is associated with 
systemic inflammation (increased levels of interleukin [IL]-1α, IL-2, IL-6, and tumor 
necrosis factor-alpha [TNF-α]). Some of these pro-inflammatory cytokines have been 
linked to more severe asthma phenotypes, potentially explaining the relationship between 
PTSD and worse asthma outcomes. However, biological pathways are likely only part of 
the drivers of asthma morbidity. Several observations suggest that PTSD has a stronger 
association with subjective (asthma symptoms, use of rescue medication, and quality of 
life) than objective (pulmonary function) markers of asthma morbidity, suggesting over-
perception of symptoms. Additionally, theory and empirical evidence suggest that 
inaccurate perception of asthma symptoms and maladaptive illness and medication 
beliefs in patients with PTSD may lead to lower adherence to asthma self-management 
behaviors (SMB), a key determinant of asthma outcomes. With adherence to controller 
medications being low among asthma patients in general, behavioral mechanisms may 
also contribute to the association between PTSD and increased asthma morbidity in WTC 
workers. Our goal is to examine the interaction of biology and behavior in WTC workers 
with asthma and PTSD and use this information to design and pilot test an intervention to 
improve their care. 
1) Objectives: 
Research Question: 
Our goal is to examine the interaction of biology and behavior in WTC workers with 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
2 
Revised  9/2/14 
asthma and PTSD and use this information to design and pilot test an intervention to 
improve their care. The Specific Aims are to:  
1. Assess the relationship of PTSD with systemic and airway inflammatory 
patterns in WTC workers with asthma and evaluate the association with asthma 
control 
H1a: PTSD will be associated with increased systemic levels of IL-1b, TNF-α and IL-6. 
H1b: WTC workers with asthma and PTSD will have an increased expression of sputum 
neutrophilia and IL-6 levels. H1c: Increased sputum neutrophilia and higher IL-6 levels 
will be associated with poorer disease control among WTC workers with asthma. 
2. Examine the longitudinal association between PTSD and symptom perception 
in WTC workers with asthma 
H2a: WTC rescue and recovery workers with PTSD will be more likely to over-perceive 
asthma symptoms in naturalistic settings compared to participants without PTSD. H2b: 
Associations between subjective (Asthma Control Questionnaire, use of rescue 
medications, and Asthma Quality of Life Questionnaire scores) and objective (forced 
expiratory volume in 1 second [FEV1]) measures of asthma control will be weaker among 
WTC workers with PTSD than those without PTSD. 
3. Assess the relationship between PTSD and adherence to asthma SMB 
(medication adherence, trigger avoidance, and inhaler technique) in WTC workers 
and identify the pathways linking them 
H3a: PTSD is associated with lower adherence to SMB among WTC workers with 
asthma. H3b: Asthma (identity, timeline, and cause), medication beliefs (necessity and 
concerns about controller medications), and over-perception of symptoms will mediate, 
in part, the influence of PTSD on SMB.  
4. Develop and pilot test an integrated intervention for asthma and PTSD by 
adapting the Relaxation Response Resiliency Program (3RP), a mind-body 
program, with counseling to promote asthma SMB, and education to correct over-
perception of asthma symptoms  
H4: The intervention will be acceptable to WTC workers, change beliefs about asthma, 
correct symptom over-perception, improve asthma medication adherence and quality of 
life and reduce symptoms of PTSD. We are currently seeking approval for the 
observational portion of the study only. We will request IRB approval for the 
interventional (pilot) phase at a later date, in advance of commencing the pilot. 
 
2) Background 
SIGINIFICANCE: Importance of the Problem: Multiple studies have shown a high 
prevalence of asthma in WTC rescue and recovery workers, local residents, and 
passersby.3-6,28-31 Using data from the National Health Interview Survey (NHIS), we 
found that WTC workers have twice the risk of asthma compared to the general United 
States (US) population.31,32 Data from the WTCHP shows a 28% cumulative incidence of 
asthma 9 years after September 11, 2001 among WTC workers.1 These studies show 
that asthma is the most prevalent respiratory condition among WTC rescue and 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
3 
Revised  9/2/14 
recovery workers.  
WTC workers with asthma include individuals with prior history of the disease and new 
cases of irritant-induced asthma.4 Many workers with preexistent asthma developed 
worsening symptoms after WTC-related exposures (WTC-exacerbated asthma). Other 
workers developed new asthma symptoms without latency during or after WTC 
exposure and were diagnosed with irritant-induced asthma.33 Multiple cases of new 
onset asthma among WTC workers have been reported in the years following exposure 
to the WTC site; characterization of these cases has been more difficult. Despite this 
potential heterogeneity, these conditions are frequently grouped in clinical practice as 
WTC-related asthma and managed similarly. 
Studies found substantial burden of asthma morbidity in WTC workers and exposed 
community members, with reports of poorly-controlled in 34% and very poorly-controlled 
symptoms in 35% of exposed individuals.5 Increased risk of emergency department (ED) 
visits and hospitalizations as well as poor quality of life in WTC workers with asthma 
have been reported, showing a major impact on health.5  
Scientific Premise of Project: PTSD is Associated with Increased Asthma 
Morbidity in WTC Workers: Prevalence of psychological symptoms in WTC-exposed 
populations is high;1,3,34-37 with PTSD reported as the most common  (~30%) mental 
health condition.1,2 Studies have also found high rates (25-35%) of PTSD comorbidity in 
WTC workers with asthma.3,38,39 Mental health conditions and PTSD in particular, have 
been associated with increased asthma morbidity.5,6 We found that WTC workers with 
PTSD had worse asthma control, increased healthcare use, and poorer quality of life 
(see preliminary data). Similarly, a study of WTC workers indicated that severity of 
PTSD symptoms predicted new onset and worsening of asthma.40 Data from studies in 
the general population have also shown that PTSD is associated with higher asthma 
morbidity.16,19,41-43 In summary, studies have documented a high level of overlap 
between asthma and PTSD in WTC workers and other exposed populations and have 
documented that PTSD is a major contributor to increased asthma morbidity. However, 
the underlying mechanisms explaining this relationship remain unknown. 
Potential Biological Pathways Linking PTSD and Asthma Morbidity: The impact of 
PTSD extends to multiple organ systems as a consequence of changes in the 
hypothalamic-pituitary axis, the autonomic nervous system, and the immune system.44-52 
These PTSD-associated systemic alterations may impact asthma morbidity. PTSD is 
associated with a basal low-grade systemic inflammation, in particular, increased 
plasma levels of pro-inflammatory cytokines such as interleukin (IL)-1α, IL-2, IL-6, tumor 
necrosis factor-alpha (TNF-α and decreased IL-4, IL-5 (“Th2-cytokines”).7-10 Airway 
inflammation, a central feature of asthma, may be modulated by enhanced systemic 
inflammation as that observed in PTSD.8,12-15 Major asthma endotypes, which describe 
asthma subtypes based on inflammatory mechanisms, include allergic, intrinsic (non-
atopic), and noneosinophilic asthma.53,54 Allergic asthma is characterized by airway 
eosinophilia driven by TH2-dominant inflammation. Noneosinophilic asthma is 
characterized by airway neutrophilia has been associated with refractory disease, 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
4 
Revised  9/2/14 
severe exacerbations, and increased risk of intubation.55-58 Key cytokines driving 
neutrophilic asthma include IL-1β, IL-6 and IL-17, which are elevated in patients with 
PTSD.51 IL-6 directs and stabilized T-cells towards a Th17 subset,59-62 which can then 
recruit and activate of neutrophils.63-66 Therefore, systemic inflammatory changes 
associated with PTSD, may worsen asthma outcomes by driving a neutrophilic asthma 
phenotype. Identification of the biological pathways underlying worse asthma in patients 
with comorbid PTSD has important implications for disease management including 
indications for inhaled corticosteroids (ICS) and new biological drugs and may offer new 
alternative targets for therapy.67,68  
Symptom Perception in Asthma Patients with Comorbid PTSD: Effective asthma 
SMB requires the patient to recognize and respond (use of rescue medication, contact 
physician, etc.) to their symptoms.69,70 Self-monitoring of symptoms is also key for 
assessing response to treatment and thus, developing effective self-regulatory 
mechanisms (i.e., ICS linked to improved symptoms; see theoretical framework). 
Unfortunately, the symptoms that asthma patients experience do not always align with 
objective measures of their airway obstruction.71-81 Experiments have identified 3 asthma 
symptom perception phenotypes that have important clinical implications: symptom 
under-perceivers, normal perceivers, and over-perceivers.78,82-84 Prior studies have 
shown a strong relationship between misperception of symptoms and increased asthma 
morbidity.77,85-88 
While PTSD is associated with increased objective and subjective asthma morbidity 
markers, the associations with subjective measures are stronger.16,18 We found that 
PTSD had strong associations with disease control measures and quality of life in WTC 
workers with asthma.17 However, the association with FEV1 was weaker (see preliminary 
data). Other studies had similar findings.16-20 These data strongly suggest that over-
perception of symptoms may be prevalent among WTC workers with PTSD and may 
contribute to increased asthma morbidity and complicate SMB. 
Our hypotheses for over-perception of symptoms among WTC workers with PTSD is 
based on Janssens’s cognitive-affective model of symptom perception.89 A central factor 
in this model is negative affect common among patients with PTSD.90-93 Janssens’s 
model89 proposes that negative affect will be linked with over-perception of symptoms 
via an associative learning mechanism. Because asthma exacerbations cause a 
negative affective state,94 an association between such a state and asthma symptoms 
develops in patients with PTSD. As a consequence, subsequent negative emotional 
states due to PTSD may results in the report of severe asthma symptoms in the 
presence of mild or no airway obstruction. The effect of negative affect is most 
pronounced on the affective component (i.e., unpleasantness dimension) of dyspnea. 
Thus, PTSD patients may perceive more asthma symptoms due to perceptions of 
unpleasant sensations of dyspnea.  
PTSD is also characterized by a disruption in the ability to regulate emotions,91,96-98 
which can lead to exaggerated emotional reactions to asthma-symptoms, in turn leading 
to symptom magnification. One relevant cognitive vulnerability factor common to PTSD 
and asthma is anxiety sensitivity, the tendency to catastrophically misinterpret the bodily 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
5 
Revised  9/2/14 
sensations associated with anxious arousal (e.g., shortness of breath or chest pounding) 
as threatening.99,100 Anxiety sensitivity is more common among patients with asthma, 
strongly implicated in the experience of dyspnea, and associated with poor asthma 
control,101-105 and greater behavioral avoidance.106 Recent work by Dr. Gonzalez 
(Consultant) indicates that anxiety sensitivity, physical concerns in particular, plays a 
significant role in understanding the PTSD-asthma symptom link in WTC workers (see 
preliminary data).  
Assessing Asthma Symptom Perception: Symptom perception is typically measured 
in laboratories by self-reported respiratory symptoms while inducing airway constriction 
with histamine or methacholine.78,82,107 However, this approach produces biased data 
because it generates anxiety and primes patients for certain reactions.82,84,107,108 In 
contrast, measurements in naturalistic settings (e.g., their home), as we propose to do, 
is a validated method87,109 that reduces the emotional threat of the test environment and 
omits pharmacological techniques and devices that may generate anxiety.77  
PTSD May Negatively Impact Asthma SMB: Asthma self-management encompasses 
several complex behaviors such as adherence to controller medications, adequate 
inhaler technique, use of action plans, allergen avoidance, and avoiding tobacco 
exposure that are critical for adequate disease control. Adherence to controller 
medications in particular, is a factor that heavily influences the outcomes of 
asthmatics.110-112 Studies conducted in the general population and our preliminary data 
from WTC workers shown that only ~50% of patients with asthma adhere to controller 
therapy or other SMB.25-27,113-117  
Mental health conditions are associated with low adherence to chronic disease SMB.118-
120 PTSD, in particular, has been strongly associated with low treatment adherence in 
multiple chronic diseases.21,23,24,121 With smoking being an important part of asthma self-
management, it is of special concern that higher rates of smoking have been reported 
among WTC workers with PTSD.122,123 Thus, low adherence to SMB may mediate, in 
part, the association between PTSD and increased asthma morbidity. However, there is 
limited data regarding the relationship between PTSD and asthma SMB in the general 
population or among WTC workers, in particular.  
Theoretical Framework: Pathways Mediating the Influence of PTSD on SMB: We 
will use the Self-regulation Model (SRM) to guide our exploration of the relationship 
between PTSD and asthma SMB via illness beliefs, emotional representations and 
symptoms perception (Figure 1 and 5).124-127 According to the SRM, people with chronic 
illness, like asthma, compare their somatic sensations (i.e., symptoms) to their “normal” 
self, and interpret deviations from “normal” in relation to their mental model of their 
illness, which in turn guides their SMB. Appraisal of the efficacy of their actions (i.e., 
improved asthma control) serves as a feedback loop to reinforce or modify SMB. The 
SRM posits five domains of cognitive representations of illness: identity (disease labels), 
cause (etiology and triggers), timeline (chronicity), consequences (perceived impact), 
and control (extent to which an illness can be controlled). For example, if asthma 
patients accurately perceive their respiratory symptoms (identity) and believe asthma is 
persistent (timeline) they will engage in SMB. The SRM also predicts that patients will be 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
6 
Revised  9/2/14 
adherent if they learn, via feedback loops, that their asthma medications can prevent 
symptoms (controllability). Emotional responses to asthma (i.e., worry, upset, or 
anxious) also influence SMB.128-134 The framework of the SRM is highly useful for 
identifying the modifiable beliefs and emotional mechanisms which underlie behaviors 
worth targeting for self-management support interventions.127 
We expect that PTSD may impact asthma SMB in several ways. WTC workers with 
PTSD may magnify asthma symptoms (identity) when they are actually experiencing 
negative emotions. Over-perception of symptoms could be a major barrier for 
internalizing positive feedback loops about medication effectiveness, leading to low 
adherence. WTC workers with PTSD and asthma may also misinterpret the causes of 
their asthma symptoms and thus, avoid situations that trigger the physical sensations 
they fear. Paradoxically, decreasing the frequency of PTSD symptoms via avoidance of 
perceived (not actual) asthma triggers may contribute to illness representations that 
focus more on this maladaptive avoidance, and less on SMB. Some patients view 
asthma as a chronic (timeline) inflammatory condition (cause), which requires adherence 
to daily ICS. Data from non-WTC asthma populations shows that patients with PTSD are 
more likely to view asthma as an acute, episodic disease.135 This ‘acute’ representation 
of asthma has been associated to low medication adherence.128 Patients with PTSD also 
tend to feel out of control (due to unexpected symptoms and catastrophic thoughts) and 
have lower self-efficacy, which has been linked to low ICS adherence.136-138  
According to the SRM, emotional responses also influence SMB. As discussed above, 
patients with PTSD have emotional regulation difficulties; thus, strong negative 
emotional reactions to asthma may deplete WTC workers’ self-regulatory resources 
managing emotions to the detriment of asthma SMB.139 SRM has also shown that 
medication beliefs strongly predict ICS adherence.130,140 Negative affect in workers with 
PTSD may extend to patients’ beliefs about ICS (e.g., side effects, dependence, etc.) 
negatively influencing adherence.133,141 Moreover, patients with PTSD may avoid asthma 
medications and awareness of symptoms because these factors may serve as trauma 
cues or reminders of 9/11, triggering memories of their WTC traumatic experiences. 
Thus, this copying style (avoidance) may lead to low medication adherence.22,142 
Absence of Interventions Integrating PTSD and Asthma Management: Despite the 
strong link between asthma and PTSD in WTC workers, there are no interventions 
aimed at managing both conditions. Dr. Gonzalez is conducting a randomized clinical 
trial (RCT) to evaluate an integrative mind-body treatment, the 3RP, to improve the 
management of PTSD and lower respiratory symptoms in WTC workers (see preliminary 
data).143-145 The 3RP is an 8-session group-based program that seeks to promote the 
physiological, emotional, cognitive and behavioral effects of the relaxation response.146 
The 3RP program focuses on 3 major areas to decrease stress and build resiliency: 1) 
eliciting the relaxation response via sustained mental focus with an attitude of open 
receptive awareness; 2) promoting stress awareness and decreasing reactivity, which 
involves identification of the 5 components of one’s stress response (thoughts, emotions, 
physical reactions, behaviors, and relationship changes) and learning skills (e.g., 
cognitive restructuring) to change these components; and 3) increasing use of adaptive 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
7 
Revised  9/2/14 
strategies by focusing on skills to promote positive growth and self-efficacy in response 
to stress. However, this intervention was not specifically developed for WTC workers 
with asthma and thus, does not address misperception of symptoms or disease SMB.  
 
3) Setting of the Human Research 
The study sites will include New York City (the Mount Sinai Hospital [MSH]) 
and Queens (Queens College – Northwell Health). 
The research at Mount Sinai will take place in the Center for Advanced Medicine 
Building at 17 East 102nd St., New York, NY 10029. The research at Queens 
College will take place at the Northwell Health Queens World Trade Center 
Health Program located at 97-77 Queens Boulevard, Rego Park, NY 11374. 
4) Resources Available to Conduct the Human Research 
The study cohort will consist of a sample of 400 WTC workers with asthma enrolled in 
the MSH or Queens World Trade Center Health Programs. There will be 300 subjects 
enrolled at MSH and 100 at Queens. Dr. Wisnivesky will be responsible for overseeing 
data collection activities and quality of data collected. For the observational cohort study 
(Aims 1-3), we selected validated tools and electronic measures that are known to be 
highly valid and reliable. Data will be collected using electronic forms with built in logic 
patterns to minimize data entry errors. Dr. Wisnivesky will train research assistants in 
survey administration techniques and appropriate maneuvers for assessing lung function; 
Drs. Katz and Gonzalez will train social workers or psychology graduate students in 
administration of the psychiatric interviews. We will randomly select 10% of audiotaped 
recordings of psychiatric interviews for Dr. Katz or Gonzalez to rate for accuracy and to 
provide feedback to the graduate students. We will also conduct random checks of 10% 
of all collected data to assess for data entry errors, ranges of input values, missing data, 
and overall data quality. Similar methods will be used to monitor data collected as part of 
the pilot RCT (Aim 4). Study team members will meet monthly to review progress in 
recruitment goals, review preliminary results, and identify and resolve emerging 
problems. 
 
Research staff will include: 
Name                                             Title 
Dept./Institution/Company 
     
Juan Wisnivesky, MD, MPH       PI             Medicine/ISMMS 
Laura Crowley, MD  
      Co-I 
Preventive Health/ISMMS 
Paula Busse, MD 
 
      Co-I      
Clinical Immunology/ISMMS 
Rachel Yehuda, MD  
      Co-I 
Psychiatry/ISMMS 
Craig L. Katz, MD 
 
      Co-I 
Psychiatry/ISMMS 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
8 
Revised  9/2/14 
 
 
 
 
 
 
Non-Key Personnel involved in study will be managed by the PI. Requisite certifications and 
records for these individuals will be included in the Regulatory Binder and Financial Conflicts of 
Interest will be reported on Sinai Central.  
 
Qualifications of Key Personnel: 
 
Dr. Wisnivesky is a Professor of Medicine and Chief of the Division of General Internal 
Medicine of the Mount Sinai Health System. He is a clinical researcher with expertise in 
asthma and COPD epidemiology, chronic disease self-management, and lung cancer. 
Dr. Wisnivesky has considerable experience conducting large observational cohort 
studies including and ongoing study of WTC workers with asthma. He was also involved 
in the Data Coordinating Center of the WTC program and participated in Steering 
Committee meetings, oversaw data management processes, and led or collaborated in 
several manuscripts summarizing the long-term health conditions among WTC workers. 
He is PI of a U01 grant to conduct a project evaluating WTC workers, has been PI of a 
phase I-II NIH-funded randomized controlled trial evaluating a novel herbal medicine for 
asthma, and MPI of two grants to assess self-management behaviors among COPD 
patients. He received a K award from the federal Agency for Healthcare Research and 
Quality to identify determinants of medication adherence and outcomes among inner-city 
asthmatics. He has also been involved in several inpatient, outpatient and physician 
studies assessing the treatment and outcomes of inner-city asthmatics.  
 
Dr. Crowley is an Assistant Professor in the Department of Preventive Medicine at the 
Icahn School of Medicine at Mount Sinai. She has worked as a clinician in the WTCHP 
since 2006 and serves as the Deputy Director of the Data Coordination Center since 2008. 
In her role as Deputy Director, she oversees the revision of clinical examination 
components, data capturing protocols, and is involved in organizing multiple operational 
and scientific activities. She is also a practicing clinician in the WTC Treatment Program. 
Dr. Crowley has published several manuscripts reporting on the health of WTC responders 
and has collaborated with Dr. Wisnivesky on prior projects. 
 
Dr. Busse’s research has focused upon the study of chronic airway inflammation in 
asthma. Her K08 funding centered upon the role of TNF-α in airway mucus metaplasia in 
mouse models of asthma. As an internist and a T. Franklin Williams Scholar, her 
research expanded to the study of asthma in older patients. Her laboratory developed 
and characterized a murine model of allergic asthma using aged mice. To expand these 
studies into human disease, she has evaluated airway inflammatory markers in older vs. 
younger patients with asthma, supported by an NIH R21 grant on which Dr. Wisnivesky 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
9 
Revised  9/2/14 
was a Co-Investigator. She has published extensively in the area of asthma 
epidemiology, inflammation, and allergic markers. 
 
Dr. Yehuda is the director of the Mental Health Patient Care Center and founder and 
director of the PTSD program of Medicine at James J. Peters VA Medical Center (JJP 
VAMC). She oversees a research laboratory dedicated to neuroendocrine and 
genetic/epigenetic assays with a particular focus on PTSD, and she has broad 
experience conducting research with the range of biological measures used in this study. 
Her research has produced about 300 peer-reviewed publications. 
 
Dr. Katz is an Associate Professor of Psychiatry at the Icahn School of Medicine at 
Mount Sinai. He co-developed and directed the WTC Worker/Volunteer Mental Health 
Screening and Treatment Program, a collaboration between Disaster Psychiatry 
Outreach and the Icahn School of Medicine at Mount Sinai that was partnered with a 
federally funded medical screening and treatment program for 9/11.  By 2007, the 
program had become successful enough to be incorporated into the National Institute of 
Occupational Safety and Health’s funding of what eventually became known as the WTC 
Medical Monitoring and Treatment Program. He has considerable expertise evaluating 
the mental health impact of disasters including the WTC terrorist attacks. He has 
collaborated with Dr. Wisnivesky in the ongoing cohort study of WTC workers with 
asthma. 
 
 
 
a) Recruitment Methods 
Source of potential subjects: 
The study cohort will consist of a sample of 400 WTC workers with 
asthma enrolled in the MSH or Queens WTCHPs. We will invite 
participants in our prior WTC-asthma cohort (HSM#12-00422; consent 
included language authorizing contact for future studies) as well as recruit 
new study subjects. 
 
Recruitment of potential subjects: 
Potential participants with a diagnosis of asthma will be identified from the 
WTCHP database and our prior WTC cohort study (HSM#12-00422; 
consent included language authorizing contact for future studies).  The 
research team will send out a letter from the study‘s PI, Dr. Wisnivesky, or 
an investigator who is a practicing physician at the WTCHP sites. 
Participants will have 1 week to respond to the letter. If the research team 
does not hear back from the participant after 1 week, then we will call the 
participant to offer participation in the study.  WTC workers who agree to 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
10 
Revised  9/2/14 
participate will be contacted by a research assistant (RA) who will explain 
the study and schedule an in-person assessment.   
 
b) Inclusion and Exclusion Criteria 
Inclusion Criteria: Participants will be 18 years of age, have a diagnosis of asthma 
made by a health care provider, and speak English or Spanish. Exclusion Criteria: 
WTC workers will be excluded if they have chronic obstructive lung disease (COPD) 
or other chronic respiratory illness. Additionally, individuals with a history of heavy 
smoking (15 pack-years) will be excluded because of the possibility of undiagnosed 
COPD. Current smokers with be included in the study if their cumulative smoking 
history does not exceed this threshold.  
 
c) Number of Subjects 
A total of 400 patients will be enrolled over a 3-year period and followed 
for 1 year.  At the ISMMS site, we will recruit 300 patients.  At the 
Queens College site we will recruit 100 patients. 
d) Study Timelines 
The study will take place from September 1, 2016 to August 31, 2021.  
Participants will be followed for 12 months with in-person interviews at 
baseline, 1 month, 6 months and 12 months. 
 
 
 
 
 
 
e) Study Endpoints 
N/A 
f) Procedures Involved in the Human Research 
For the observational phase of the study, sources of data will be the 
interviewer-administered surveys, the WTCHP database, spirometry, 
airway and peripheral blood samples, the AM2 device, electronic 
Table 5. Study Timeline 
TASK 
Yr 1 
Yr 2 
Yr 3 
Yr 4 
Yr 5 
Study Preparation 
 
 
 
 
 
 
 
 
 
 
Baseline interviews  
 
 
 
 
 
 
 
 
 
 
Follow-up interviews 
 
 
 
 
 
 
 
 
 
 
Data Analysis 
 
 
 
 
 
 
 
 
 
 
Pilot RCT 
 
 
 
 
 
 
 
 
 
 
Dissemination  
 
 
 
 
 
 
 
 
 
 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
11 
Revised  9/2/14 
adherence monitors, and the electronic medical record (EMR). Interviews 
will be conducted in English or Spanish in person (as required for several 
measures) at baseline, 1, 6, and 12 months (See Table below). 
Summary of Measures and Timing of Data Collection 
Variables 
Instrument(s) or Measure(s) 
Source 
Timing of Collection 
(Month) 
OUTCOMES 
 
 
0 
1 
6 
12 
Inflammatory Markers 
 
 
 
 
 
 
Sputum Cell Differential 
Sputum induction/cytospins 
Sputum 
 
 
 
 
Sputum Cytokines 
Multiplex assays of sputum supernatant 
Sputum 
 
 
 
 
Systemic Cytokines 
Multiplex assays 
Plasma 
 
 
 
 
Symptoms Perception 
 
 
 
 
 
 
Symptom Perception 
AM2 electronic devices 
 
 
 
 
 
Self-management  
 
 
 
 
 
 
Objective Adherence  
Smartinhaler, Smart disk 
 
 
 
 
 
Self-reported Adherence 
Medication Adherence Report Scale 
Horne160 
 
 
 
 
Other Behaviors  
Inhaler technique, trigger avoidance, etc. 
Van Beerendonk190 
 
 
 
 
Asthma Morbidity 
 
 
 
 
 
 
Airway Obstruction 
Forced expiratory volume at 1 second/PEF 
Spirometry/AM2 
 
 
 
 
Asthma Control 
Asthma Control Questionnarie 
Juniper197 
 
 
 
 
Use of Beta-2 Agonists 
Doser electronic devices 
 
 
 
 
 
Resource Utilization 
Emergency Department use, Hospitalizations 
EHR/self-report 
 
 
 
 
Quality of Life 
Asthma Quality of Life Questionnaire 
Juniper210 
 
 
 
 
PREDICTORS 
 
 
 
 
 
 
PTSD 
SCID, PTSD Checklist 
First200 
 
 
 
 
Asthma Health Beliefs 
Asthma-Illness Perception Questionnaire 
Weinman211 
 
 
 
 
Asthma Medication Beliefs 
Beliefs about Medications Questionnaire 
Horne130 
 
 
 
 
Anxiety Sensitivity 
Anxiety Sensitivity Index 3 
Taylor209 
 
 
 
 
Asthma History 
Age of onset, intubations, asthma regimen, etc. 
 
 
 
 
 
Medication Regimen 
Chart review and self-report 
 
 
 
 
 
Comorbidities 
Charlson Index 
Charlson212 
 
 
 
 
Depression 
SCID/PHQ-9 
Spitzer204 
 
 
 
 
WTC exposures 
Exposures at the WTC site, protection 
WTCHP survey 
 
 
 
 
Sociodemographics 
Age, sex, race/ethnicity, language, health literacy 
NHIS, NVS213 
 
 
 
 
PEF: peak expiratory flow, NAS: National Asthma Study, NAEPP, EHR: electronic health record, PTSD: posttraumatic stress 
disorder, SCID: Structured Clinical Interview, PHQ-9: Patient Health Questionnaire, NIHS: National Health Interview Survey, 
NVS: New Vital Sign 
 
Outcome Measures (Appendix A and Table 3): A. Systemic and Airway Inflammatory 
Markers: Peripheral Pro-inflammatory Cytokines: To measure peripheral cytokine, blood will be 
collected at baseline, 1-, 6, and 12-months, in the morning (8-9 AM, prior to eating) to decrease 
potential confounding factors of diurnal variation and diet,7 using methods employed by 
members of our research team.176 Samples will be processed with 30 minutes of collection by 
centrifugation and separation of plasma into aliquoted samples stored at -80°C. Plasma 
cytokine levels will be analyzed using a multiplex assay (Milliplex Human Th17 Magnetic Bead, 
Eotaxin and IL-8, Billerica, MA, USA) as in our prior studies.177 Briefly, samples, standards, and 
controls will be added to the appropriate wells. The premixed magnetic beads will be added to 
each well and incubated on a plate shaker for 18 hours at 4°C.  After washing, detection 
antibody will be added and incubated on a plate shaker for 1 hour, followed by Strepaviden-

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
12 
Revised  9/2/14 
Phycoerythrin for 30 minutes. The plate will be run on the Luminex 200 system (Luminex Corp., 
Austen, TX) and data will be analyzed using the MILLIPLEX Analyst Software (EMD Millipore 
Corp., Billerica, MA). 
Sputum Inflammatory Markers: To limit participant burden, we will only perform sputum 
induction at the 1-month visit. However, we will have repeated measures of systemic cytokines, 
which will allow for longitudinal assessment of the association of PTSD-related inflammation 
and asthma control. During the baseline visit, we will collect data on ICS use and monitor 
adherence for 4 weeks. Using this information, we will be able to control for the potential effect 
of ICS and sputum inflammatory markers. Sputum will be collected on 175 participants (see 
power calculation) following standardized protocols.178,179 Briefly, subjects will be pre-treated 
with 360 µg of albuterol followed by spirometry to ensure an FEV1 ≥60% predicted. They will 
then undergo a 12-minute sputum induction with PEF monitoring for participant safety. Subjects 
will be excluded from sputum induction if: 1) their FEV1 <60% predicted (for safety reasons), 2) 
they had a respiratory tract infection <4 weeks prior to sputum induction, or 3) an asthma 
exacerbation or oral corticosteroid use <4 weeks prior to sputum induction. We will weight 
sputum samples, add a dithiothreitol (DTT) containing Sputolysin Reagent (Calbiochem, San 
Diego, CA, USA; 1 ml to 1 gram of sample), and then will place samples in a 37°C shaker for 15 
minutes. The sample will be washed with PBS and spun down; the supernatant will be stored at 
-80°C.   
Sputum Cell Differential: Cytospins will be prepared and stained with Diff-Quick (Dade 
Diagnostics of PR, Aguada, PR) for differential cell counts. The sputum cell differential will be 
determined by counting ~500 white blood cells on cytospin slides, excluding samples with a cell 
viability <50% and >20% squamous cells.178,180 Sputum eosinophilia will be defined as >2%;181-
183 sputum neutrophilia as ≥40%.180 Sputum Cytokines: Sputum supernatant will be analyzed for 
a panel of cytokines using the multiplex assay as described above.   
Asthma Symptom Perception: We will use the AM2 computerized peak flow monitor (ERT 
Corporation, Philadelphia, PA; Figure 2) to assess symptom perception by comparing actual 
and perceived PEF values for 4 weeks following the baseline, 6- and 12-months 
interviews.77,109,184 Following a well validated protocol, RAs will train participants to enter the 
PEF estimate (step 1) and then perform the PEF effort (step 2). To help them estimate their 
PEF, the RA will attach a colored sticker to the AM2 showing the participant’s s predicted PEF 
values (based on age, sex and height) that correspond to the go (green), caution (yellow), and 
danger (red) zones of asthma control (Figure 3).172 After entering their estimated PEF, 
participants will perform 3 maximal effort blows, with 2 minute rests between each. The actual 
peak flow values of each blow will not appear on the device. The AM2’s acoustic alarm will 
remind them to use it in the morning and evening.  

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
13 
Revised  9/2/14 
The asthma risk grid (Figure 4) was developed to quantify symptom perception 
accuracy.77,109,172,184,185 Each objective PEF is plotted against the corresponding subjective 
estimate of PEF to generate a percent of objective personal best. Patients’ estimates are 
categorized in the accurate, under-perception, and over-perception zones, and must be at least 
10% higher or lower than the actual PEF value (to ensure that estimates close to the accurate 
zone are not classified as inaccurate) to be considered in these zones, respectively. Each 
participant’s symptom perception will be characterized as the percent of time they spend within 
each perception zone. The percentage of estimates in the over-perception one will be the main 
study measure. Home Peak Flow Meter (PFM) use: We will ask patients with their own PFMs 
not to use them while they are using the AM2. In our prior studies, <5% of participants used a 
PFM ≥1 time/week.  
 
C. Asthma SMB: will be based on NIH guidelines.172 Asthma Controller Medication Adherence: 
Electronic Monitoring: We will objectively measure ICS adherence using the Smartinhalers 
(Nexus6, Franklin, OH) or Doser electronic device (Meditrack, MA) for metered dose inhalers 
and the Smartdisk (Nexus6, Franklin, OH) for dry powder inhalers for 4 weeks after each in 
interview. RAs will attach the monitoring device to the inhaler, and patients will return them by 
mail in a pre-stamped envelope (95% return rate among 317 participants in our prior studies). 
Adherence will be defined medication use on ≥70% of days prescribed, a commonly applied 
convention.160,186 In secondary analyses, we will examine adherence as a continuous measure. 
Self-reported: The Medication Adherence Rating Scale (MARS) will be used to measure self-
reported adherence.160,187-189 We found the MARS to have good psychometric properties both in 
English and Spanish.160 2) Inhaler technique: We will assess inhaler technique on placebo 
devices using validated checklists.190-192 3) Action Plans: Use of action plans will be evaluated 
with questions from our prior research.128,153 4) Asthma Trigger Avoidance: We will use validated 
items from the National Asthma Survey193 to document allergen exposure and actions taken to 
limit exposure. We will also assess tobacco smoking behaviors and second hand exposure to 
tobacco. 5) Routine Asthma Care: will be defined as ≥2 routine (non-urgent) annual visits for 
asthma. 
 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
14 
Revised  9/2/14 
Asthma Morbidity: Objective Measures: Spirometry: FEV1 is a direct, reproducible, physiologic 
measure of asthma activity.194 We will follow standard performance guidelines.195,196 Electronic 
Peak Flow Monitoring: As described above we will collect detailed PEF data from AM2 devices 
for 4 weeks after each visit. 
Subjective Measures: Asthma Symptoms: Asthma control will be assessed with the Asthma 
Control Questionnaire (ACQ).197,198 It is available in English and Spanish and has excellent 
validity. Use of Beta2-agonists: Over-perception may be associated with increased use of quick 
relievers. Thus, we will use self-reports as well as Doser devices to objectively capture use of 
these medications for 4 weeks after each interview. Acute Resource Utilization: will include self-
reported and electronic data on unscheduled office and ED visits and asthma-related 
hospitalizations. We will identify visits occurring at outside institutions by self-report and request 
external records. Although resource utilization can be considered a more objective measure it 
also is influenced by subjective perceptions concerning the need to seek help. Asthma quality of 
life: We will use the validated Mini Asthma Quality of Life Questionnaire (AQLQ); available in 
English and Spanish.199 
Independent Variables (Table): PTSD: Structured Clinical Interview (SCID): The SCID is 
considered the gold-standard psychiatric interview.200 The Bilingual version of the SCID will be 
used at the baseline, 6- and 12-month visits as the semi-structured psychiatric interview.200-202 A 
psychology graduate student or social worker will administer the PTSD and the mood disorders 
modules. Dr. Katz and Gonzalez will provide supervision for all diagnostic issues. Quality 
Assurance: We will randomly select 10% of audiotaped recordings for Drs. Katz or Gonzalez to 
rate for accuracy and to provide feedback to interviewers. Patient Safety: If patients with active 
suicidal ideation are identified, the PIs will be notified to determine the need for an emergency 
psychiatric consult. Participants with PTSD will be given a list of counseling sites. Additionally, 
we will ask for patients’ consent (signed HIPAA authorization) to alert their physicians about the 
SCID results after a lag of 4-6 weeks (to be able to assess the impact of PTSD on symptom 
perception and SMB). We will collect detailed data on medications for PTSD and/or depression 
by self-report and EMR review. 
Other Mental Health Assessments: PTSD Checklist: PTSD symptom severity will be measured 
using the PTSD Checklist-Civilian Version,203 a self-report questionnaire that assesses 17 
symptoms based on diagnostic criteria for PTSD. Probable PTSD will be defined as a score ≥50 
and endorsement of each of the 3 criteria required for a diagnosis of PTSD. 2) Patient Health 
Questionnaire (PHQ-9): The PHQ-9 has excellent validity, good sensitivity and specificity, it is 
sensitive to change over time, and has been used in the WTCHP.34,204  
Illness and Medication Beliefs: Asthma Health Beliefs: We will assess asthma-related beliefs 
using the Brief-Illness Perceptions Questionnaire (B-IPQ).205,206 This is an English and Spanish 
validated instrument that includes items for the 5 cognitive domains of the SRM. We will use 
items from the full IPQ assessing emotional representations of asthma. We will also include 
items measuring illness and medication beliefs specific about WTC-related asthma (e.g., “WTC 
asthma is more difficult to control”) used in our WTC cohort study. Medications Beliefs: We will 
use the Beliefs about Medicines Questionnaire (BMQ),129,130,207,208 an English and Spanish 
validated 10-item scale that measures beliefs about asthma controller medication in 2 
subdomains: necessity and concerns (reliability: 0.80). Self-Efficacy: Self-efficacy regarding 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
15 
Revised  9/2/14 
asthma management and control will be assessed using items adapted from questionnaires 
used in our prior studies.128,133 
Anxiety Sensitivity: We will use the Anxiety Sensitivity Index-3,209 a validated scale to assess 
fear arousal-related anxiety sensations along 3 domains: somatic, social, and cognitive 
concerns.209 
Covariates: Asthma History: Items about asthma history will include: age of onset and relation 
to 9/11, oral steroid use, history of intubation, and past ED visits and hospitalizations. We will 
obtain detailed information regarding onset of symptoms in relation to WTC-related exposure 
and whether symptoms or medication requirements worsened after WTC work among workers 
with preexisting asthma (WTC-exacerbated asthma).4 Individuals with onset of asthma 
symptoms shortly after 9/11 exposures (no latency), will be categorized as having irritant-
induced asthma. Patients with insidious onset of asthma symptoms within 1-2 years of exposure 
will be classified as having late onset asthma, possible irritant-induced;4 those with asthma 
onset >2 years post exposure will be coded as having late onset asthma, probably not irritant-
induced. At each visit, we will determine participants’ asthma medications and their dosages by 
self-report and by querying the EMR. The concentration of total and allergen-specific (house 
dust mites, molds, cockroaches, cats, and mice) IgE will be used to assess sensitization to key 
indoor allergens in peripheral blood.214-216 Information on home environmental exposures will be 
obtained from validated questionnaires.217,218 We will also collect data on asthma symptoms in 
relation to current job and environmental triggers encountered in the current workplace. 
Medical Comorbidities: History of physician diagnosis of sinusitis, rhinitis, GERD, and OSA will 
be assessed using questions from the WTCHP survey.219 Body mass index will be assessed 
using height and weight data collected during spirometry. We will use Charlson’s Index to 
assess the workers’ burden of comorbidities.212 Smoking and Alcohol Use: will be measured 
with items from the National Health Interview Survey (NHIS).220 
WTC-Related Exposures: We will use data collected as part of the WTCHP to characterize 
WTC exposures of study participants. Variables include time of arrival, exposure to the dust 
cloud, work location, total duration of exposure, and type of activities performed. Exposure will 
be categorized in four levels based on the total time a responder spent working at the WTC site, 
exposure to the cloud of debris, and work on the pile of debris.1  We will also assess for 
psychological stressors including shift length, exposure to body parts, and fear for personal 
safety. Use of respiratory protection will be assessed with data collected as part of WTCHP 
survey.  
Demographics and Cultural Factors: Basic demographics will include age, sex, race/ethnicity, 
education, income, and occupation.220  Health literacy: The Newest Vital Sign is a 3-minute 
assessment validated in English and Spanish.213  Access to Care: We will obtain information on 
insurance status and query subjects about whether they participate in the WTCHP and have a 
regular doctor.  
g) Specimen Banking 
Data specimens will be stored in an identifiable manner using indirect identifiers.  The patient 
study identifiers will be linked to the blood sample.  The file that links the study identifiers with 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
16 
Revised  9/2/14 
the patient is stored on a secure server that is encrypted and password-protected and 
encrypted.  
The specimens with be stored in Dr. Paula Busse’s laboratory in the Icahn Medical 
Institute at 1425 Madison Avenue 
 
.  The specimens will be 
stored in -80 degree freezer and locked securely to minimize the risk of a breach of 
confidentiality.  
These specimens will not be released to any additional requestors until a formal request 
has been submitted to the IRB and Dr. Wisnivesky. 
 
h) Data Management and Confidentiality 
Data Management and Security: We will use standard IRB-approved and HIPAA 
compliant measures to maintain patient confidentiality, privacy, and data security. Data 
privacy and security procedures will include: a) training staff on data sensitivity and 
protocols for safeguarding confidentiality; b) storing and processing samples and 
sensitive hardcopy in a secured, centralized location; c) securing sensitive hardcopy in 
locked files when not in use; d) removing names, addresses, and other direct identifiers 
from samples, hardcopy and computer readable data after they are not necessary for 
participant tracking and then using codes for subsequent identification of subjects; e) 
destroying all identifiable linkages to data after data accuracy has been verified and final 
analyses have been completed; and f) using restricted logon identification and password 
protection computer protocols for all computerized entry, retrieval, and analysis. 
 
All study data will be entered on a weekly basis into a computerized database. A 
computerized record system will be used to help the research assistants to track the 
follow-up interviews. To preserve participant confidentiality, study subjects will be 
assigned code numbers. Using these codes, none of the collection forms will contain the 
names or medical record number of the participants. There will be a master list matching 
the names of the participants to the code numbers. The list will be secured in a locked 
cabinet. All data will be stored on mainframe and terminals will be password protected 
and maintained in locked offices. 
 
Data Analyses: We will obtain a HIPAA waiver to use de-identified data to compare 
non-respondents and those lost to follow-up to study participants by age, gender and 
ethnicity. Descriptive Analyses: We will use the chi-square test, t-test or Wilcoxon test to 
compare the baseline characteristics of WTC workers with and without PTSD. Then, we 
will examine the distribution of dependent variables and, as appropriate, consider 
transformations to reduce non-normality of continuous outcomes.  
Aim 1. Assess the relationship of PTSD with systemic and airway inflammation in WTC 
workers and evaluate the association with asthma control: We will use the chi-square or 
Wilcoxon test to compare the distribution of airway inflammatory cells and systemic and 
sputum cytokine levels from WTC workers with and without PTSD. We will use a 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
17 
Revised  9/2/14 
generalized linear model to assess the association of PTSD with sputum eosinophilia or 
neutrophilia (logit link), or cytokine levels (identity link) after controlling for possible 
confounders such as age, sex, race/ethnicity, ICS dose (calculated after adjusting for 
adherence), asthma onset in relation to WTC exposure, BMI, comorbidities, and 
depression. We will calculate the false discovery rate from the p-values to control for 
testing of multiple cytokines.223 Then, we will assess the unadjusted association of 
plasma and sputum cytokine levels as well as the associations of airway eosinophilia, 
neutrophilia, and cytokines levels with measures of asthma control using correlation 
coefficients or Wilcoxon test. The adjusted relationship of inflammatory markers 
(systemic and sputum) and asthma control measures over time will be assessed using 
generalized estimating equation (GEE) models (logit or identity link and autoregressive 
correlation structure for repeated measures over time). The model will include an 
interaction between inflammation markers (e.g., neutrophilia, etc.) and PTSD status to 
assess for potential effect modification (i.e., differential effect in subjects with vs. without 
PTSD). Finally, we will fit a fixed effects model (i.e. limited to within subject variability) to 
assess the longitudinal effect of changes in systemic cytokines levels on asthma 
morbidity makers. 
We will use structural equation modeling (SEM; see details below) to test whether 
systemic inflammation, leading to airway neutrophilia and high IL-6 levels, mediates the 
association between PTSD and increased asthma morbidity. Following the MacArthur 
approach224 for assessing mediation, main effects as well as interactions between PTSD 
and inflammatory markers will be included as predictors of asthma morbidity.225,226 The 
analyses described above will establish if PTSD has a significant effect on the mediators 
(i.e., inflammatory markers), which is the first step of mediation. What is then needed is 
to also show that these factors are also associated with asthma morbidity measures 
while controlling for PTSD. Building a SEM including inflammatory markers, PTSD and 
an interaction variable of PTSD with the potential mediators, while controlling for other 
confounders, will provide a formal test of mediation.  
 
 
 
 
 
 
 
 
 
 
Table 3. Power Calculations for Aim 1 
Outcome 
Proportion/ 
Mean among 
Participants 
without 
PTSD 
∆ Proportion/ 
Mean for 
Participants 
with PTSD 
Sample 
Size 
for 
80% 
Power 
Sputum 
Neutrophilia 
0.25 
0.30 
106 
0.25 
0.25 
149 
Sputum 
Eosinophilia 
0.50 
0.25 
107 
0.50 
0.57 
157 
IL-6, pgr/ml 
4 (2) 
2 
67 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
18 
Revised  9/2/14 
Power Calculations: Assumptions about the expected retention rate (≥80%), the 
prevalence of PTSD (~30%) and the distribution of inflammatory markers were derived 
from our preliminary data and the literature.1,7,8 Under these assumptions, with 175 
participants undergoing sputum induction, the study will be powered to test Aim 1 
hypotheses (Table 3). 
Aim 2. Examine the longitudinal association between PTSD and symptom perception in 
WTC workers with asthma: We will calculate the proportion of blows that each 
participant over-estimate using AM2 data. A probit transformation will be applied to 
normalize the proportion of over-perceived guesses; differences in the distribution of the 
transformed variable at each time point in participants with and without PTSD  will be 
assessed with a t-test.227 We will use a GEE model to assess the association between 
PTSD and symptom perception over time.228  We will then fit a fixed effects model (i.e., 
limited to within subject variability) to assess the longitudinal effect of changes in PTSD 
symptoms (PCL scores) on symptom perception. We will repeat these analyses 
adjusting for potential confounders as described above. 
We will also assess the correlation between subjective (ACQ scores, use of beta2-
agonists, AQLQ scores) and objective (FEV1) measures of morbidity separately in 
asthmatics with and without PTSD and apply a Fisher’s z’ transformation to assess if the 
association varies between these groups. Then, we will fit a GEE model with ACQ 
scores (or use of beta2-agonists/AQLQ) as the dependent variable and as predictors, 
FEV1, PTSD status, and an interaction between PTSD and FEV1. In this model, the 
interaction term will test whether the association between objective and subjective 
measures varies according to the participant’s PTSD status.  
Power Calculations: We estimated rates of over-perception and asthma morbidity from 
our prior studies or the literature.27,109,154,155,168,229 We adjusted the sample size for the 
expected correlation of measurements within a participant (interclass correlation 
coefficient ≥0.8).230 These analyses showed that with 400 patients, the study will have 
>90% power to detect a 10% increase in the probability of over-perception in participants 
with PTSD. We also evaluated the power to identify whether the regression coefficients 
for the association between the ACQ/AQLQ scores and FEV1 is different for patients with 
vs. without PTSD (equivalent to testing an interaction). These analyses showed that with 
400 subjects (and 80% retention), the study will have an 82% power to detect a 
difference or 1 unit between the slopes of patients with and without PTSD.  
Aim 3. Assess the relationship between PTSD and adherence to asthma SMB in WTC 
workers and identify the pathways linking them: Medication adherence analyses will be 
restricted to patients prescribed controller medications (>80% of the sample based on 
prior studies). Primary analyses will use electronic adherence measures; secondary 
analyses will use MARS scores and other SMB. The univariate association of adherence 
and PTSD will be assessed using a chi-square test. Multivariable analyses will use a 
GEE model (logit link function) to control for potential confounders as listed above. We 
will use similar approaches to assess the associations of potential mediators (over-
perception of symptoms, anxiety sensitivity, and illness and medication beliefs, Figure 5) 
of the relationship between PTSD and medication adherence.  

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
19 
Revised  9/2/14 
Latent Growth Curve Modeling (LGCM): We will employ LGCM approaches to test the 
mediation model presented in Figure 5.231,232 The analysis will involve longitudinal 
assessment of asthma SMB across 3 time points (0, 6, and 12 months). We hypothesize 
that both time-varying covariates (e.g., illness and 
medication beliefs) and time-invariant covariates 
(e.g., age, sex, etc.) will predict asthma SMB 
assessed at these time points. We also 
hypothesize potential lagged effects of covariates 
at earlier time points. As a first step, we will 
identify the measurement model for the latent 
variables using confirmatory factor analysis. 
Specifically, we will create latent variables 
representing random effects intercepts and 
slopes for illness and medication beliefs (IBt0, IBt6, 
and IBt12; where t0 represents baseline illness 
beliefs scores), anxiety sensitivity and asthma 
SMB measures. Illness representations will be 
measured by 5 independent factors (i.e., identity, 
timeline, etc.), medication representations by 2 factors (i.e., necessity and concerns), 
and anxiety sensitivity by 3 factors. Emotional representations will be modeled as a 
single domain. This approach will allow us to test specific pathways. This model will also 
include the control variables listed above. We will estimate slope and intercept 
parameters using a Weighted Least Squares Mean-Variance adjusted (WLSMV) 
estimator, which provides robust estimates for complex models with modest sample 
sizes. We will test this measurement model for absolute fit using Chi-square and 
RMSEA statistics.232,233  
Next, an overall unconditional model will be fitted to identify the growth trajectory across 
time. To that end, we will fit a growth function for anxiety sensitivity, symptom 
perception, illness beliefs, and asthma SMB using linear, quadratic, and unstructured 
models. Relative model fit will be evaluated based on the: χ² index (>.05), the 
comparative fit index (>.97), the root mean squared error of approximation 
(RMSEA<.05), and the weighted root mean square residual when using WLSMV 
(WRMR<.90). The most parsimonious model with the best fit will be retained. Finally, we 
will fit the full structural model, including the hypothesized relationships. For example, 
PTSD will be included as a predictor of asthma SMB. To address the possible 
mediational effects of anxiety sensitivity, symptom perception, illness and medication 
beliefs on the relationship between PTSD and asthma SMB, we will fit models to 
estimate both direct and indirect effects, first separately, and then combined. Lagged 
effects of the time-varying predictors, as well as the effects of the latent growth variables 
themselves (intercept, slope, and their random effects) will be evaluated as potential 
mediators; we will also be able to assess models of complete vs. partial mediation.128 
Relative fit, as well as estimates of effect size will be calculated, along with Sobel tests 
and Monte Carlo CIs to evaluate the mediational hypotheses.234  

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
20 
Revised  9/2/14 
Integrating Biological and Behavioral Pathways: Finally, we will employ LGCM to 
characterize the interrelation and relative contribution of biological and behavioral 
pathways linking PTSD and asthma morbidity (Figure 1).  
Power Calculation: Power calculations for LGCM were based on published methods.235 
Effect size in this approach is defined as a null and alternative hypothesis value of the 
RMSEA index, which we hypothesize to be 0.05 (adequate fit) and 0.03 (good exact fit), 
respectively. Power in SEM can be conceptualized as a function of sample size and the 
number of parameters to be estimated in the model, relative to the information provided 
in the overall variance-covariance matrix of the observed variables. The estimated power 
is based on a proposed sample size of 360 (assuming that 80% of total sample will be 
on controller medications) with an 80% follow-up rate, yielding estimated power >0.80 for 
an average effect of 0.10 with an alpha of 0.05. Overall, despite the challenges of 
estimating a priori power for SEM approaches, especially those involving growth models, 
we believe the proposed study will be adequately powered to address this aim. 
We will request a separate IRB approval prior to the intervention phase of the study 
that is outlined in Aim 4. 
 
Aim 4. Develop and pilot test an integrated intervention for asthma and PTSD by 
adapting the 3RP, with counseling to promote asthma SMB, and education to correct 
over-perception of symptoms: Overview: Based on the results of Aim 3, we will script 
messages aimed to counter beliefs linked to low adherence and to support those that 
promote better asthma SMB; these messages will be incorporated into specific sessions 
of the 3RP (Appendix D). If Aim 2 shows symptom over-perception in participants with 
PTSD, we will also integrate strategies to train individuals to more accurately perceive 
symptoms by providing feedback.87 We will conduct a proof-of-concept pilot RCT in a 
subset of 60 WTC workers with asthma and PTSD who have completed their 12-month 
study visit to test the enhanced 3RP for PTSD and asthma. We are currently seeking 
approval for the observational portion of the study only. We will request IRB approval for 
the interventional (pilot) phase at a later date, in advance of commencing the pilot. 
Correcting Asthma Symptom Over-perception: As part of the intervention, participants 
will receive an AM2 device. Before each daily PEF measurement, they will be instructed 
to guess their PEF with no advantage for guessing too high vs. too low. After the 
maneuver, participants will be able to view, in the display of the AM2 device, their PEF 
values and will be instructed to compare their results with their pre-effort estimated 
values. Similar PEF feedback training strategies have been shown to be effective in 
children with asthma.87 We will also explain to the consequences of over-perception 
(e.g., over-use of β-2 agonists) and links with asthma and medication beliefs, and SMB. 
This approach is consistent with adaptive perspective taking and cognitive restructuring, 
which are taught in the 3RP. In addition, we will provide psychoeducation on anxiety 
sensitivity (if linked to over-perception) using mindfulness skills and relaxation training, 
which are taught in the 3RP, and shown to be effective in patients with PTSD.236,237 
Integrating Asthma SMB into 3RP: To guide design of the SMB support components of 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
21 
Revised  9/2/14 
the intervention, we will apply the SRM, which has been used to build coping strategies, 
knowledge, and skills in patients with low adherence to self-management tasks by 
addressing beliefs that influence SMB.127 Illness and medication beliefs having the 
strongest associations with SMB will be addressed in the intervention. Cognitive 
restructuring and adaptive perspective taking methods will be incorporated into the 3RP 
sessions to address misconceptions about asthma in WTC workers with PTSD. For 
example, patients may feel that WTC-related asthma cannot be controlled or that 
arousal symptoms resulting from PTSD are specific to asthma. These views can be 
“reconstructed” by teaching patients about the effective management of asthma and how 
to differentiate PTSD and anxiety symptoms from asthma symptoms. In addition, 
according to the SRM, patients interpret symptoms in relation to their mental model of 
illness and these assessments in turn guide their SMB. Appraisal of the efficacy of their 
actions reinforces or modifies SMB. Thus, we will work on helping WTC workers develop 
accurate perceptual discrimination of symptoms arising from asthma, thereby creating a 
process in which they search for the appropriate signals to initiate and appraise the 
effects of self-management thus, generating effective self-regulatory feedback controls. 
We will also address avoidance behaviors – specifically, avoidance of asthma SMB 
because of their association with the WTC disaster (i.e., trauma-cues). Mindful 
awareness training included in the 3RP will focus specifically on reducing these 
avoidance behaviors.  
Refinement of New Components: We will conduct qualitative interviews with ~10 
participants who completed the 12-month interview to evaluate and refine the new 3RP 
components. During the audio-recorded sessions, we will share the educational 
messages and counselling strategies and ask participants to provide feedback.238 
Training and Fidelity: Masters-level clinicians will be trained to deliver the adapted 3RP 
intervention by Dr. Gonzalez. Dr. Gonzalez will provide weekly supervision and review 
audio-taped sessions for treatment fidelity. Pilot RCT Procedures: Dr. Gonzalez will 
adapt the 3RP procedural manual to incorporate new components. We will use data 
from the 12-month interview to identify WTC workers with asthma and PTSD for the pilot 
(N=60). Eligible WTC workers who agree to participate will be randomized 1:1 (using 
adaptive randomization to balance the number of participants in each arm with respect 
to age, sex and PTSD symptoms severity) to the intervention vs. an attention control 
group. Intervention Group: Participants randomized to the adapted 3RP condition will 
participate in the manualized 8-session group -based program (4-8 participants per 
group). They will also receive an unblinded AM2 device during the first 6 weeks of the 
intervention. Attention Control: Control patients will participate in an 8-session group-
based program of similar time and therapist attention. The control intervention will 
consist of educational sessions covering general asthma knowledge (Asthma 1-2-3)239 
group-based support. They will receive blinded AM2 devices. Outcome Assessment: A 
telephone follow-up survey 4 weeks after the last session will be administered to assess 
the patient’s illness and medication beliefs, anxiety sensitivity, their adherence to asthma 
SMB, and PTSD symptoms. Data Analysis: 1) Quantitative Assessment: Differences in 
illness (B-IPQ), medication beliefs (BMQ), anxiety sensitivity (ASI-3), adherence to 
asthma medications (MARS), and PTSD symptoms (PCL) will be assessed using a t-test 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
22 
Revised  9/2/14 
or Wilcoxon test, as appropriate. 2) Qualitative Feedback: The post-intervention 
interview will also include open-ended questions for: a) recollection of specific messages 
from the counseling, b) satisfaction and perceived usefulness, and c) ways of improving 
the messages and their delivery.  Power: The study will have >80% power to identify a 
clinically meaningful differences in IPQ, BMQ, ASI, MARS, and PCL scores for 30 
patients in each study arm (n=60).  
 
i) Provisions to Monitor the Data to Ensure the Safety of subjects 
Data Safety and Monitoring Plan 
 
We have established a monitoring plan for the observational phase of the study (Aims 1-
3). 
 
Overview 
 
A. Brief description of the purpose of the study: The goal of the proposed study is to 
examine the inflammatory and behavioral mechanisms underlying the association 
between PTSD and increased asthma morbidity among WTC rescue and recovery 
workers. 
B. Adherence statement: The Data Safety Monitoring Plan (DSMP) outlined below for 
the proposed study will adhere to the protocol approved by the MSH and Queens 
College IRBs.  
C. Data quality and management:  Principal investigators will review all data collection 
forms on an annual basis for completeness and accuracy of the data as well as 
protocol compliance.  A statement reflecting the results of the review will be sent to 
the NIOSH in the annual report. 
 
Adverse Events 
 
A. Adverse event grading  
1. Attribution scale: An adverse event is defined as both an expected side effect 
that is of a serious nature, or an unexpected side effect/event regardless of 
severity. All events will be graded as to their attribution (unrelated to protocol, 
or possibly, probably, or definitely related to protocol). Any event that is 
reported to either a principal investigator or their designated research 
associates by the subject or medical staff caring for the subject and which 
meets the criteria will be documented as such. 
2. Expected risks: As detailed in the consent form, the expected risks include: 
 Discomfort caused by personal questions asked in the survey.  
 Distress resulting from the questions related to PTSD or depressive 
symptoms.  
 Complications of the breathing test which may include dizziness or light-
headedness due to deep respirations. 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
23 
Revised  9/2/14 
 Complications of blood draws which may include pain, discomfort, 
bruising, dizziness, and faint. 
 Distress resulting from the sputum induction, which may feel like it’s 
worsening their asthma.  
 
These risks are considered to be minimal and are addressed in the protocol 
and consent form. In order to further safeguard the mental health of the study 
participants we will: (1) Any participant who becomes discomforted or 
distressed will be given the opportunity to speak with a clinical psychologist, 
social worker or qualified medical professional; (2) we will track the occurrence 
of these events and after two incident reports are filed for a participant, they 
will be flagged for a consultation with a counselor (clinical psychologist, social 
worker or qualified medical professional). Complications from the breathing 
test will be tracked. A clinician will be called in the event of breathing problems 
following spirometry, or dizziness or faint following phlebotomy. Albuterol 
inhaler will be given before the sputum collection to try to prevent worsening 
asthma, and respiratory status will be monitored throughout the procedure for 
signs of worsening or trouble breathing, at which point the test will be stopped 
and participants will be given more albuterol. A physician (PB) will oversee all 
sputum inductions and will therefore be present for any treatment needed. The 
albuterol inhaler can cause the participant to feel hand shaking, dizziness, fast 
heart beats, or feeling nauseous. 
 
B.  Plan for reporting both anticipated and unanticipated adverse events: All expected 
and unexpected serious adverse events will be reported according to protocols 
defined by the NIOSH.  We will expedite reporting of serious adverse events to the 
MSH or Queens College IRBs, where applicable, when such events are unexpected 
(within 7 calendar days when life-threatening or fatal; within 15 calendar days for all 
other unexpected serious adverse events). 
 
The research staff, including project managers and research coordinators, will be 
trained to identify and report all adverse events, regardless of severity, as well as 
problems of data security, to the PI. Weekly study conference calls will involve the 
PI, Queens College site PI, project manager, and research coordinators. One of the 
main purposes of the calls will be to ensure patient and study safety and ensure 
compliance with monitoring and reporting. Toward these objectives, every meeting 
will include: (1) a report of the number and nature of all adverse events occurring 
during the previous week (monitoring study safety); (2) a discussion of the adverse 
events and development of a plan or change in study protocol to prevent similar or 
related adverse events, where possible (minimizing research-associated risk); (3) 
initiation of the process of reporting adverse events and unanticipated problems to 
the IRB, if they have not yet been reported already (adverse event reporting); (4) 
identification of breaches of confidentiality of participant data or problems of data 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
24 
Revised  9/2/14 
security, and discussion and development of plans to prevent problems of data 
security (ensuring data security). The protocol will be modified as needed to ensure 
patient safety and data security.  
 
Safety Review Plan and Monitoring 
 
A. Safety reviews. During the observational study (considered low risk), a data safety 
monitoring board will not be employed.  The PI will have overall responsibility for 
overseeing the safety of all study participants in this phase of the study.  Locally, Dr. 
Wisnivesky will have primary responsibility for the safety of patients recruited at 
MSH. Dr. Markowitz (site PI) will have responsibility for patients recruited through the 
Queens site. During the pilot study (considered greater than minimal risk), a Data 
Safety Monitoring Board will oversee the safety of the study participants (see below).   
B. Annual review. The PI will review this protocol on a continuing basis for subject 
safety and include results of the review in the annual progress reports submitted to 
the IRB and NIOSH. 
C. Annual report. The annual report will include a list of adverse events. 
D.  Content of annual report. The annual report will address: (1) whether adverse event 
rates are consistent with pre-study assumptions; (2) reason for dropouts from the 
study; and (3) whether all participants met entry criteria. 
 
Data Safety and Monitoring Board (DSMB) 
 
We will convene a DSMB to oversee participant safety for the pilot intervention proposed 
for Aim 4. (We will also submit a new IRB for this phase of the study.) 
 
A. Brief description of the DSMB: The board members will meet prior to implementation 
of the pilot RCT of the intervention to review the study protocol and measures to 
ensure that adequate protections and the plan to monitor for adverse events are 
adequate. They will then meet every 6 months after implementation of the pilot to 
review data, including the following elements: recruitment rate, study withdrawal, 
reasons for withdrawal, adverse events, impact of intervention on beliefs and 
behaviors, asthma symptom perception and symptoms of PTSD. 
B. Qualifications of DSMB members:  The board will consist of a mental health expert, a 
pulmonologist, and a biostatistician. The board will not serve as co-investigators on 
the study. A DSMB chair will be identified and will convene the board yearly to review 
the study and accumulated data.   
C. Role and Responsibilities of the DSMB:  The DSMB is an independent group 
advisory to the PI and is required to provide recommendations about starting, 
continuing, and stopping the study.  In addition, the DSMB is asked to make 
recommendations, as appropriate, to the PI about: 
 
Efficacy of the study intervention  

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
25 
Revised  9/2/14 
 
Benefit/risk ratio of procedures and participant burden 
 
Selection, recruitment, and retention of participants 
 
Adherence to protocol requirements 
 
Completeness, quality, and analysis of measurements  
 
Amendments to the study protocol and consent forms 
 
Participant safety 
 
Notification of and referral for abnormal findings 
The DSMB will monitor patient safety, consider new scientific or therapeutic 
developments that could impact safety or trial ethics, and make 
recommendations to continue, terminate, or modify the trial based on interim 
analyses.  The DSMB will specifically review: 1) hospitalization and mortality 
rates; 2) study disenrollment unrelated to death; 3) and any participant and 
healthcare provider concerns.  The DSMB may recommend stopping the trial if 
there is clear evidence of harm or overwhelming benefit. Adverse events will 
include disruption of previously established regular care such that the 
participant’s health is jeopardized or excessive burden created by the time 
required to participate in the study.  The DSMB can recommend changes in 
study protocol or termination of the study if it concludes the study design causes 
disruptions in patient-provider continuity which jeopardized the health of the 
study subject or if the study imposes excessive burden on participants.  Finally 
the DSMB, at the request of the sponsor, will review accrual and evaluate study 
progress towards meeting recruitment targets. 
 
The DSMB will review safety and data information yearly. Should a temporary or 
permanent suspension of the study occur, in addition to the PPHS, we will report 
this to NIOSH. 
 
j) Withdrawal of Subjects 
Participants may choose to withdraw from the study at any time without 
any penalty.  If participants decide to withdraw from the study, they need 
to contact the PI or research staff.  If participants wish to withdraw their 
permission for use and disclosure of any of their protected health 
information for research, they must do so in writing to the PI at the 
address on the consent.  
5) Risks to Subjects 
The proposed study will use survey instruments and interventions that are similar to 
those used by us and other investigators previously. We do not anticipate any significant 
physical, psychological, or social risk to the study participants. Research subjects could 
become fatigued during the interview. To limit this risk we will provide multiple 
opportunities for breaks. Distress may also result from questions relating to depressive 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
26 
Revised  9/2/14 
symptoms. A clinical psychologist, social worker or qualified medical professional will be 
sought in PTSD or cases where participants become upset or wish to speak to someone 
further. The protocol to address patients with suicidal ideation is described below (see 
Protections Against Risks). The expected risks also include dizziness related to 
performing a pulmonary function test. Those who report dizziness will be promptly 
instructed to discontinue the test, and a qualified medical professional will be sought if 
symptoms persist. Subjects may experience pain, discomfort, bruising, dizziness or faint 
from blood draws. There is also a very small risk of infection at the needle insertion site. 
To reduce these risks, all blood draws will be performed by a trained phlebotomist. A 
physician will be called to evaluate any subject who appears faint. Additionally, 
participants will cough during sputum induction, which may feel like it’s worsening their 
asthma. Albuterol inhaler will be given before the sputum collection to attenuate the risk 
of worsening asthma, and respiratory status will be monitored throughout the procedure 
for signs of worsening or trouble breathing, at which point the test will be stopped and 
participants will be given more albuterol. A physician (PB) will oversee all sputum 
inductions and will therefore be present for any treatment needed. The albuterol inhaler 
can cause the participant to feel hand shaking, dizziness, fast heart beats, feeling 
nauseous, or produce rash, and/or hives. All risks of participation will be explained to 
subjects and included in the written informed consent document.  
 
We anticipate no adverse events arising from the intervention we propose to test for Aim 
4, which consists of counseling to promote better asthma self-management behaviors 
(SMB), education to correct over-perception of asthma symptoms, and an adapted 
version of the Relaxation Response Resiliency Program to improve symptoms of PTSD. 
We will obtain physicians’ consent to approach their patients, and notify them that we 
may randomize their patients to an intervention that involves asthma SMB and PTSD 
counseling. If physicians believe that it is unsafe for their patients to participate in 
asthma SMB and PTSD counseling, they may choose to decline patient participation. 
 
6) Provisions for Research Related Injury 
N/A 
7) Potential Benefits to Subjects 
Participants may enjoy the opportunity to talk about how their illness and or 
experiences impact their life or to simply express their opinions. Participant 
may also find satisfaction in contributing to a research effort intended to 
ultimately improve the health of WTC workers and other exposed 
populations. Individuals participating in the pilot study may benefit from the 
counseling related to asthma SMB and PTSD. They may also find satisfaction 
in contributing to a research effort intended to ultimately improve the health of 
people like them. 
8) Provisions to Protect the Privacy Interests of Subjects 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
27 
Revised  9/2/14 
Confidentiality 
 
A. Protection of subject privacy. To preserve patient confidentiality, study subjects will 
be assigned code numbers. Using these codes, none of the collection forms will 
contain the names or medical record number of the participants or other personal 
identifiers. There will be a master list at each institution matching the names of the 
participants to the code numbers. The list will be safely stored in secure network 
drives.  Paper-based consent and HIPAA documents will be stored in locked cabinets 
within locked offices, separate from the master lists.  All electronic data will be stored 
on mainframe servers, and terminals and Tablet PCs will be password protected and 
maintained in locked offices.  
B. Database protection. Participant information will only be accessible to the PI, project 
manager, and research coordinators associated with the research. Data collected on 
Tablet personal computers (PC) will be uploaded on a daily basis to mainframe 
servers supported by the local institutions and encrypted using Bitlocker software.  
These data will lack personal identifiers other than a study identification code.  
Following the upload, the data on the Tablet PCs will be deleted.  Encrypted data 
from the Queens WTCHP site will be transferred electronically to Mount Sinai, 
which will serve as the data coordinating center, on a weekly basis. The transferred 
data will be free of personal data that qualifies as PHI.  All data received at the data 
coordinating center (Mount Sinai) will be entered into a computerized database and 
stored in encrypted files on a mainframe server that is backed up nightly by the 
Mount Sinai Hospital IT Department. 
C.  Confidentiality during adverse event reporting. Adverse event reports and annual 
summaries will not include subject-identifiable material. Each will include the coded 
identification number only.  
9) Economic Impact on Subjects 
N/A 
10) 
Payment to Subjects 
Patients will be paid up to $280 for their participation in the observational portion of the 
study. They will receive $50 for the baseline, six-month and twelve-month interviews after 
the completion of each interview. They will receive $90 for completion of the sputum test at 
the 1-month follow-up visit. They will receive $10 for returning the electronic monitoring 
devices (Peak Flow Monitor and the electronic medication monitoring device) each time they 
are used: after the baseline, 6-month, and 12-month interviews. The electronic monitoring 
devices following the baseline interview will be returned at the 1-month interview, in person. 
The electronic monitoring devices following the 6-month and 12-month interviews will be 
returned by mail using a pre-stamped envelope provided by the researchers. Subjects may 
also receive $10 for completing the follow-up phone call after the baseline interview. 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
28 
Revised  9/2/14 
If selected to participate in the pilot study, subjects may receive up to $160 for their 
participation in this pilot.  Upon completing the pilot study baseline interview they will 
receive $70 for their time and effort.  Upon completing the follow-up interview for the pilot 
study they will receive $20 for their time and effort. This will be given to them at the end of 
the study in cash unless otherwise requested. At their completion of the pilot study, they will 
receive $70 for your time and effort.  
 
 
11) 
Consent Process 
Setting: 
Consent will take place in a private room in the outpatient clinics of the 
Pulmonary or General Internal Medicine (IMA) Departments at Mount Sinai 
Hospital. 
 
Process: 
Only members of the research team who have been fully trained in the protocol will 
obtain the treating provider’s permission to recruit potential patients.  
 
Research Interview 
Payment 
 
 
Observational Study 
 
Baseline Interview 
$50 
Follow-up Phone call after baseline 
$10 
1-month interview (including sputum test) 
$90 
Return of electronic monitoring devices (from baseline)  in 
person 
$10 
6-month Interview 
$50 
Return of electronic monitoring devices (from 6-month interview) 
by mail 
$10 
12-month Interview 
$50 
Return of electronic monitoring devices (from 12-month 
interview) by mail 
$10 
Total (Observational Study) 
$280 
 
 
Pilot Study 
 
Pilot Baseline 
$70 
Follow-up Phone Interview 
$20 
End of Study 
$70 
Total (Pilot Study) 
$160 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
29 
Revised  9/2/14 
Using the WTC STMP patient list, the PI and/or research assistant will approach the 
physician who provides care to the patient, and ask him/her if they agree for the PI or 
research assistant to call their patient over the telephone to explain them details about the 
study, screen them for eligibility, and offer them the oppourtunity to participate in the 
research study. An explanation and letter with details about the study will be given to 
treating phsycisians. In addition, a letter will be sent, from their primary care physician, 
to the patient by mail prior to calling them. In this letter, their primary care physician will 
give details about the studyin addition to the PI’s office phone number, in case the 
subjects have any questions or concerns.  The screening questions that would be asked 
over the phone are the following: 1) has any physician ever told you that you have 
asthma, any other lung disease; and 2) have you ever smoked cigarettes regularly. 
Patients who screen eligible will be offer participation in the study. If the subject agrees 
to participate, a date and time will be set in the IMA clinic for which a private room will 
be used to explain in detail the study and the consent.   
 
Before including a patient in the study, the investigator or research assistant will verify 
that the given consent documents are written in the language that the subjects can 
understand them. Also the investigator or research assistant will verify that the subjects 
understand the objectives of the study, the type of information that will be collected, 
when and how it will be collected, and that participation in this study is voluntary. This 
will be done by asking the patient to describe to us what they understand the study entails 
and also to state the potential risks and benefits of the study.   
 
Non-English Speaking Subjects 
For subjects non- English speaking subjects who speak Spanish, the bilingual 
research assistant will be conducting the consent in Spanish. The bilingual 
research assistant will be using the approved PPHS consent form template in 
Spanish. The bilingual research assistant will ask the patient to describe to us 
what they understand the study entails and state the potential risks and benefits of 
the study in Spanish.  
 
Waiver of Informed consent 
 
The waiver of informed consent that is being requested is for a research report 
query from the WTC STMP database.  This will allow the research staff to 
identify potentially eligible adults being seen in the Mount Sinai through the 
WTC STMP database. This will also permit the research staff to find out the time 
and date of the research subjects next appointment so he/she can be approached. 
This search is necessary, so the PI and/or RA can identify patients with asthma 
that are seen in the Mount Sinai Medical Center.  This informed consent waiver is 
only for the identification of patient’s with a physician diagnosis of asthma and 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
30 
Revised  9/2/14 
their scheduled appointment.  This informed consent waiver is to identify patients 
with a diagnosis of asthma followed in the Mount Sinai Medical Center Internal 
Medicine or Pulmonary clinic and to know of their next appointment. This 
information is already known by the research subject and will not provide any 
additional information to him or her. 
Additional information: 
1. The research poses minimal risk of harm to the subjects.  
2. The waiver of informed consent does not adversely affect the rights and welfare 
of the subjects.  
3. This is a non-invasive survey-based study. Questions pertain to demographic 
characteristics and self-reported health behaviors only. No drugs or treatments are 
involved.   
4. None of the findings will be directly pertinent to the individual research subjects. 
5. The research is not FDA-regulated. 
6. The research does not involve non-viable neonates. 
7. The research is not conducted or funded by the Department of Defense (DOD). 
8. The research involves no more than minimal risk to the subjects. 
9. Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation. 
Data/specimen banking is not contingent upon participation in the study.  Each 
patient can choose to have 10 cc of venous blood or 20 cc of venous blood, with the 
additional 10 cc to keep for future research studies.  There are no limits that are to be 
placed on the intended future use of the specimens.  Participants will be provided 
with the option to opt out of data/specimen banking and also to store the blood 
samples anonymously. 
 
12) 
Process to Document Consent in Writing 
The team will adhere to "SOP-HRP-090 Informed Consent Process" and "SOP-HRP-091 
Written Documentation of Informed Consent 
 
Written informed consent will be obtained from each subject at entry into the study 
using the standard PPHS consent template. Informed consent is obtained by the 
following process: 
 Subject review the study consent form. 
 PI, site PIs or research delegates speak with the subject to review the consent, 
confirm subject’s understanding, and answer any questions. 
 Once the investigator is convinced that the subject verbally demonstrates 
understanding and agrees to the process, the consent is signed by the subject 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
31 
Revised  9/2/14 
and the research delegate. Individuals authorized to obtain written consent are 
the PI, site PIs, co-investigators, and assigned research delegates specifically 
designated by the principal investigators to work on this project. 
 
13) 
Vulnerable Populations 
Include 
Exclude 
Vulnerable Population Type 
 
X 
Adults unable to consent 
 
X 
Individuals who are not yet adults 
 
X 
Wards of the State 
 
X 
Pregnant Women 
 
X 
Prisoners 
X 
 
economically or educationally 
disadvantaged persons   
 
X 
Individuals with diminished mental 
capacity 
 
14) 
Multi-Site Human Research (Coordinating Center) 
Dr. Wisnivesky will be responsible for overseeing data collection activities and 
quality of data collected. For the observational cohort study (Aims 1-3), we selected 
validated tools and electronic measures that are known to be highly valid and reliable. 
Data will be collected using electronic forms with built in logic patterns to minimize 
data entry errors. Dr. Wisnivesky will train research assistants in survey 
administration techniques and appropriate maneuvers for assessing lung function; 
Drs. Katz and Gonzalez will train social workers or psychology graduate students in 
administration of the psychiatric interviews. We will randomly select 10% of 
audiotaped recordings of psychiatric interviews for Dr. Katz or Gonzalez to rate for 
accuracy and to provide feedback to the graduate students. We will also conduct 
random checks of 10% of all collected data to assess for data entry errors, ranges of 
input values, missing data, and overall data quality. Similar methods will be used to 
monitor data collected as part of the pilot RCT (Aim 4). Study team members will 

 
Protocol Title: 
Assessing Inflammatory and Behavioral Pathways  Linking 
PTSD to Increased Asthma Morbidity in WTC Workers 
Principal Investigator 
Name/Contact Info:  
Juan P. Wisnivesky, MD, DrPH 
212-824-7567; juan.wisnivesky@mssm.edu 
Primary Contact 
Name/Contact Info 
Emily Goodman, MS 
212-824-7475; emily.goodman@mssm.edu 
Date Revised: 
07/25/16 
Study Number: 
IF# 1896970; GCO# 16-0945 
 
32 
Revised  9/2/14 
meet monthly to review progress in recruitment goals, review preliminary results, and 
identify and resolve emerging problems. 
15) 
Community-Based Participatory Research 
N/A 
16) 
Sharing of Results with Subjects 
Results will not be communicated with study participants as part of the study 
is not to influence decision making.  
 
17) 
External IRB Review History 
N/A 
 
18) 
Control of Drugs, Biologics, or Devices 
Note: The IDS has its own forms that must be completed and a review process 
that must be followed before the IDS representative will sign off on Appendix B 
for submission to the PPHS.